vol 4 4 2000 - institut de l'information scientifique et...

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.

Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).


© ATLAS - ISSN 1768-3262

Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)







Editor

Jean-Loup Huret (Poitiers, France)

Volume 4, Number 4, October - December 2000

Table of contents

Gene Section

IKZF1 (Ikaros family zinc finger 1) 179 Jean-Loup Huret

MYC (v-myc myelocytomatosis viral oncogene homolog (avian)) 181 Niels B Atkin

PIM1 (pim-1 oncogene) 183 Jean-Loup Huret

TFF1 (trefoil factor 1) 185 Catherine Tomasetto, Marie-Christine Rio

TRAF4 (TNF receptor-associated factor 4) 186 Catherine H Régnier, Catherine Tomasetto, Marie-Christine Rio

BLM (Bloom) 188 Mounira Amor-Guéret

TAF15 (TAF15 TAF15 RNA polymerase II, TATA box

binding protein (TBP)-associated factor, 68kDa) 190 Jean-Loup Huret

PRDX1 (peroxiredoxin 1) 192 Maité P Prosperi, Didier Ferbus, Gérard Goubin

PML (Promyelocytic leukemia) 193 Franck Viguié

RARA (Retinoic acid receptor, alpha) 195 Franck Viguié

ZNF146 (zinc finger protein 146) 197 Gérard Goubin

Leukaemia Section

Fibrogenesis imperfecta ossium 198 Daniel Bontoux, Michel Alcalay, Jean-Loup Huret

Chronic myelogenous leukaemia (CML) 200 Ali G Turhan




Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia V ariant (HCL-V) 203 Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky

t(9;22)(q34;q11) in CML 205 Ali G Turhan

Solid Tumour Section

Thyroid: Papillary carcinoma 209 Marco A Pierotti

Bladder: transitional cell carcinoma 212 Jean-Loup Huret, Claude Léonard

Cancer Prone Disease Section

Bloom syndrome 218 Mounira Amor-Guéret

Simpson-Golabi-Behmel syndrome 221 Hope H Punnett

Cockayne syndrome 222 Claude Viguié

Trichothiodystrophy (TTD) 223 Claude Viguié

Werner syndrome 224 Mounira Amor-Guéret

Xeroderma pigmentosum 226 Claude Viguié

Deep Insight Section

Micronuclei : Pitfalls and Problems 229 John RK Savage

Educational Items Section

Cancer Prone Diseases 234 Jean-Loup Huret

Embryology, Semiology, Dysmorphology 237 Jean-Loup Huret

Trisomy 21 244 Jean-Loup Huret, Pierre-Marie Sinet

Other Constitutional Chromosome Diseases 248 Jean-Loup Huret, Claude Léonard

Gene Section Mini Review


179



IKZF1 (Ikaros family zinc finger 1) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: August 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/IkarosID258.html DOI: 10.4267/2042/37660

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity HGNC (Hugo): IKZF1

Other names: IK1; LYF1; ZNFN1A1 (zinc finger protein, subfamily 1A, 1)

Location: 7p12

DNA/RNA Transcription 3629 bp mRNA; coding sequence: 1559 bp; 6 different splicings (--> 6 isoform proteins: ik1-ik6).

Protein Description 519 amino acids; 58 kDa; possesses 2 Zinc-finger (C2H2-type) domains: one with 4 ZnF, the second with 2 ZnF; DNA binding.

Expression Specificity for hematopoietic organs in the foetus and in the adult as well.

Localisation Nuclear.

Function Transcription regulator; can repress transcription through the recruitment of histone deacetylase complexes; role in conjunction with Aiolos; hemopoietic-specific zinc finger protein regulator of B and T-cell differentiation.

Implicated in t(3;7)(q27;p12) diffuse large B-cell lymphoma (DLCL) --> BCL6 / Ikaros Note Only 2 cases to date.

Hybrid/Mutated gene 5' Ikaros - 3' BCL6 fusion transcript; it is supposed that substitution of the promoter of BCL6 may be responsible for BCL6 deregulation.

References Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AG. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell. 1997 Dec 12;91(6):845-54

Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997;15:155-76

Nichogiannopoulou A, Trevisan M, Friedrich C, Georgopoulos K. Ikaros in hemopoietic lineage determination and homeostasis. Semin Immunol. 1998 Apr;10(2):119-25

Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C, Georgopoulos K. Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med. 1999 Nov 1;190(9):1201-14

Winandy S, Wu L, Wang JH, Georgopoulos K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J Exp Med. 1999 Oct 18;190(8):1039-48

Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples. Oncogene. 1999 Dec 23;18(56):7994-9

IKZF1 (Ikaros family zinc finger 1) Huret JL


180

Hosokawa Y, Maeda Y, Ichinohasama R, Miura I, Taniwaki M, Seto M. The Ikaros gene, a central regulator of lymphoid differentiation, fuses to the BCL6 gene as a result of t(3;7)(q27;p12) translocation in a patient with diffuse large B-cell lymphoma. Blood. 2000 Apr 15;95(8):2719-21

Koipally J, Georgopoulos K. Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. J Biol Chem. 2000 Jun 30;275(26):19594-602

This article should be referenced as such:

Huret JL. IKZF1 (Ikaros family zinc finger 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):179-180.



181



MYC (v-myc myelocytomatosis viral oncogene homolog (avian)) Niels B Atkin

Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK (NBA)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MYCID27.html DOI: 10.4267/2042/37661

This article is an update of : Larizza L, Beghini A. KIT. Atlas Genet Cytogenet Oncol Haematol 1999;3(1):1-3 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: C-MYC. Identified as the oncogene of the MC29 avian myelocytomatosis virus

HGNC (Hugo): MYC

Location: 8q24

c-MYC (8q24) in normal cells: PAC 944B18 (top) and PAC 968N11 (below) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

DNA/RNA Transcription Alternative splicing; coding sequences: 1318 and 1362 bp for proteins p64 and p67 respectively.

Protein Description 439 amino acids and 48 kDa in the p64; 454 amino acids in the p67 (15 additional amino acids in N-term; contains from N-term to C-term: a transactivation domain,an acidic domain, a nuclear localization signal, a basic domain, an helix-loop-helix motif, and a leucin zipper; DNA binding protein.

Expression Expressed in almost all proliferating cells in embryonic and adult tissues; in adult tissues, expression correlates with cell proliferation; abnormally high expression is found in a wide variety of human and rodent tumours.

Localisation Located predominantly in the nucleus.

Function The encoded myc oncoproteins are apparently transcription factors known as basic region-helixloop-helix-leucine zipper (b-HLH-Zip) proteins; like other b-HLH-Zip proteins, they modulate the expression of target genes by binding to specific DNA sequences. In this case, however, the binding requires dimerization to another b-HLH-Zip protein, namely Max (the latter can also form heterodimers with Mad as well as homodimers with itself). Myc/Max complexes activate transcription and promote cell proliferation and transformation. Mad/Max complexes, however, repress transcription and block myc-mediated cell transformation. All three complexes bind to the same DNA sequence and are competitors.

MYC (v-myc myelocytomatosis viral oncogene homolog (avian)) Atkin NB


182

Expression of c-myc is required for proliferation; it can over-ride p53-induced Gl-arrest by inducing an inhibitor of the cyclin kinase inhibitor WAFI(p2l). The latter (located at 6p2l) normally coordinates S and M phases of the cell cycle. If absent, cells with damaged DNA arrest not in GI but in a G2-like state from which they can pass through additional S phases without intervening normal mitoses (the deformed polyploid cells that result may then die by apoptosis). The uncoupling of S and M may contribute to the acquisition of the chromosomal abnormalities manifested by most tumour cells when apoptotic pathways have been circumvented.

Homology The human myc family also includes N-myc and L-myc, rather specifically implicated in neuroblastoma and small-cell lung carcinoma, respectively, in which amplified copy numbers have been found.

Implicated in Burkitt's lymphoma Hybrid/Mutated gene The gene is activated by translocation next to an immunoglobulin constant gene. Most frequently, it is positioned near the immunoglobulin heavy-chain (IgH) constant region on chromosome 14 but, in some tumours, near the light-chain region chromosome 2 (IgK) or 22 (IgL). It is now known that immunoglobulin joining enzymes may be involved in recombinations associated with a variety of chromosomal translocations in B and T cells.

Amplification has been described in many types of tumour, including breast, cervical and colon cancers, as well as in squamous cell carcinomas of the head and neck, myeloma, non-Hodgkin's lymphoma, gastric adenocarcinomas and ovarian cancer Prognosis C-myc involvement is by no means universally found in these cancers; there may be a correlation with the more advanced stages, suggesting a value as a prognostic indicator (although this has not been demonstrated in some studies for breast, ovarian and cervical cancers).

Oncogenesis C-myc gene activation (enhanced expression and/or amplification) may result from chromosomal duplication as well as translocation, and from retroviral as well as point mutation. Multiple copies of the gene may be evidenced in homogeneously staining chromosomal regions and in double minutes.

Role of c-myc in other conditions Disease

In adult respiratory distress syndrome the degree of diffuse alveolar damage and consequently the prognosis may be related to the intensity of expression of c-myc in the alveolar cells which, if severe, may contribute to deregulation of cellular proliferation and apoptosis. In endometriosis, c-myc expression is a possibly important regulator of cellular proliferation.

To be noted Note Although c-myc appears to be active in variety of tumours, it is important to realise that in common with other mechanistic pathways to cancer induction and progression no single genetic event (including c-myc deregulation) will prove to be necessary in the light of the inherent complexity and diversity of cellular pathways leading to neoplasia.

References Rappold GA, Hameister H, Cremer T, Adolph S, Henglein B, Freese UK, Lenoire GM, Bornkamm GW. c-myc and immunoglobulin kappa light chain constant genes are on the 8q+ chromosome of three Burkitt lymphoma lines with t(2;8) translocations. EMBO J. 1984 Dec 1;3(12):2951-5

Saksela K, Bergh J, Lehto VP, Nilsson K, Alitalo K. Amplification of the c-myc oncogene in a subpopulation of human small cell lung cancer. Cancer Res. 1985 Apr;45(4):1823-7

Depinho RA, Hatton K, Ferrier P, Zimmerman K, Legouy E, Tesfaye A, Collum R, Yancopoulos G, Nisen P, Alt F. Myc family genes: a dispersed multi-gene family. Ann Clin Res. 1986;18(5-6):284-9

Schenken RS, Johnson JV, Riehl RM. c-myc protooncogene polypeptide expression in endometriosis. Am J Obstet Gynecol. 1991 Apr;164(4):1031-6; discussion 1036-7

Garte SJ. The c-myc oncogene in tumor progression. Crit Rev Oncog. 1993;4(4):435-49

Roschke V, Kopantzev E, Dertzbaugh M, Rudikoff S. Chromosomal translocations deregulating c-myc are associated with normal immune responses. Oncogene. 1997 Jun 26;14(25):3011-6

Schreiber-Agus N, DePinho RA. Repression by the Mad(Mxi1)-Sin3 complex. Bioessays. 1998 Oct;20(10):808-18

Adamson A, Perkins S, Brambilla E, Tripp S, Holden J, Travis W, Guinee D Jr. Proliferation, C-myc, and cyclin D1 expression in diffuse alveolar damage: potential roles in pathogenesis and implications for prognosis. Hum Pathol. 1999 Sep;30(9):1050-7

Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999 May 13;18(19):3004-16

Ozkara HA, Ozkara S, Topçu S, Criss WE. Amplification of the c-myc oncogene in non-small cell lung cancer. Tumori. 1999 Nov-Dec;85(6):508-11


Atkin NB. MYC (v-myc myelocytomatosis viral oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):181-182.



183



PIM1 (pim-1 oncogene) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/PIM1ID261.html DOI: 10.4267/2042/37662


Identity HGNC (Hugo): PIM1

Location: 6p21.2

DNA/RNA Description 5 kb of genomic DNA; 6 exons.

Transcription 2.6 kb mRNA; coding sequence 941 bp.

Protein Description 313 amino acids, 36 kDa; protein kinase domain, ATP-binding site.

Expression Plays a role in signal transduction in blood cells.

Function Serine/threonine-protein kinase; regulated by hematopoietic cytokine receptors; synergy with c-MYC in cell proliferation and in apoptosis induction (through an enhancement of the activation of caspase-3 -like proteases; Cdc25A (cell cycle phosphatase) is a substrate for Pim-1.

Implicated in t(3;6)(q27;p21.2) diffuse large B-cell lymphoma (DLCL) --> BCL6 / PIM1 Note Only 1 case to date.

Hybrid/Mutated gene 5' PIM1 - 3' BCL6 fusion transcript; it is supposed that substitution of the promoter of BCL6 may be responsible for BCL6 deregulation.

References Selten G, Cuypers HT, Boelens W, Robanus-Maandag E, Verbeek J, Domen J, van Beveren C, Berns A. The primary structure of the putative oncogene pim-1 shows extensive homology with protein kinases. Cell. 1986 Aug 15;46(4):603-11

Meeker TC, Nagarajan L, ar-Rushdi A, Croce CM. Cloning and characterization of the human PIM-1 gene: a putative oncogene related to the protein kinases. J Cell Biochem. 1987 Oct;35(2):105-12

Mochizuki T, Kitanaka C, Noguchi K, Sugiyama A, Kagaya S, Chi S, Asai A, Kuchino Y. Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation. Oncogene. 1997 Sep 18;15(12):1471-80

Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN, Ness SA. Pim-1 kinase and p100 cooperate to enhance c-Myb activity. Mol Cell. 1998 Oct;2(4):417-25

Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y. Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway. J Biol Chem. 1999 Jun 25;274(26):18659-66

Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T. Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity. 1999 Dec;11(6):709-19

Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples. Oncogene. 1999 Dec 23;18(56):7994-9

PIM1 pim-1 oncogene Huret JL


184

Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM. Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1). FEBS Lett. 2000 Feb 4;467(1):17-21


Huret JL. PIM1 (pim-1 oncogene). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):183-184.

Gene Section Short Communication


185



TFF1 (trefoil factor 1) Catherine Tomasetto, Marie-Christine Rio

I.G.B.M.C., BP163, 1 rue Laurent Fries, 67404 ILLKIRCH, France (CT, MCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TFF1ID201.html DOI: 10.4267/2042/37663


Identity Other names: pS2

HGNC (Hugo): TFF1

Location: 21q22.3

Local order: Belongs to the TFF cluster.

DNA/RNA Description 5kb gene; 3 exons.

Transcription 600bp cDNA; coding sequence: 252 bp.

Protein Description 84 amino acids, containing a peptide signal; the 60 AA-long mature secreted peptide contains one TFF (TreFoil Factor) domain and one acidic C-terminal domain.

Expression Epithelial cells of the stomach surface.

Localisation Cytoplasmic.

Function In the maintenance of mucosa integrity; unknown at the molecular level; deficient mice develop antro-pyloric adenoma.

Homology TFF2/SP (spasmolytic peptide) and TFF3/ITF (intestinal trefoil factor).

Implicated in Disease Overexpressed in estradiol-dependent breast carcinomas; overexpressed in carcinoma of several other organs; loss of expression in half of gastric carcinomas (TFF1 is normally expressed in the stomach).

Prognosis Good prognosis factor, and marker of response to hormonal treatment in breast carcinomas.

References Foekens JA, Rio MC, Seguin P, van Putten WL, Fauque J, Nap M, Klijn JG, Chambon P. Prediction of relapse and survival in breast cancer patients by pS2 protein status. Cancer Res. 1990 Jul 1;50(13):3832-7

Lefebvre O, Wolf C, Kédinger M, Chenard MP, Tomasetto C, Chambon P, Rio MC. The mouse one P-domain (pS2) and two P-domain (mSP) genes exhibit distinct patterns of expression. J Cell Biol. 1993 Jul;122(1):191-8

Spyratos F, Andrieu C, Hacène K, Chambon P, Rio MC. pS2 and response to adjuvant hormone therapy in primary breast cancer. Br J Cancer. 1994 Feb;69(2):394-7

Lefebvre O, Chenard MP, Masson R, Linares J, Dierich A, LeMeur M, Wendling C, Tomasetto C, Chambon P, Rio MC. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science. 1996 Oct 11;274(5285):259-62

Ribieras S, Tomasetto C, Rio MC. The pS2/TFF1 trefoil factor, from basic research to clinical applications. Biochim Biophys Acta. 1998 Aug 19;1378(1):F61-77

Tomasetto C, Masson R, Linares JL, Wendling C, Lefebvre O, Chenard MP, Rio MC. pS2/TFF1 interacts directly with the VWFC cysteine-rich domains of mucins. Gastroenterology. 2000 Jan;118(1):70-80


Tomasetto C, Rio MC. TFF1 (trefoil factor 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):185.



186



TRAF4 (TNF receptor-associated factor 4) Catherine H Régnier, Catherine Tomasetto, Marie-Christine Rio

I.G.B.M.C., BP163, 1 rue Laurent Fries, 67404 ILLKIRCH, France (CHR, CT, MCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TRAF4ID204.html DOI: 10.4267/2042/37664


Identity Other names: MLN62; CART1

HGNC (Hugo): TRAF4

Location: 17q11-q12

Local order: TRAF4, Lasp1(alias MLN50), c-erbB2, MLN64, MLN51.

TRAF4 (17q11-q12) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

DNA/RNA Description 5,5 kb gene; 7 exons.

Transcription 2 kb cDNA; coding sequence: 1410 bp.

Protein Description 470 amino acids; 53 kDa; contains an amino-terminal RING finger domain, a central stretch of six putative

Zinc-binding domains (3 CART domains) and a carboxyl-terminal TRAF domain.

Expression Epithelial cells; weak ubiquitous expression in adult tissues; stronger expression level in kidney and thymus.

Localisation Cytoplasmic; nuclear when overexpressed.

Function Putative signal transducer.

Homology To TRAF proteins (Tumor Necrosis Factor Receptor Associated Factor).

Implicated in 17q11-q12 gene amplification; found in about 25% of primary breast carcinomas Prognosis Poor clinical outcome; increase risk of relapse.

References Régnier CH, Tomasetto C, Moog-Lutz C, Chenard MP, Wendling C, Basset P, Rio MC. Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptor-associated protein family, which is expressed in breast carcinoma. J Biol Chem. 1995 Oct 27;270(43):25715-21

Tomasetto C, Régnier C, Moog-Lutz C, Mattei MG, Chenard MP, Lidereau R, Basset P, Rio MC. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics. 1995 Aug 10;28(3):367-76

Bièche I, Tomasetto C, Régnier CH, Moog-Lutz C, Rio MC, Lidereau R. Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer. Cancer Res. 1996 Sep 1;56(17):3886-90

TRAF4 TNF receptor-associated factor 4 Régnier CH, et al.


187

Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. Genes Dev. 1998 Sep 15;12(18):2821-30


Régnier CH, Tomasetto C, Rio MC. TRAF4 (TNF receptor-associated factor 4). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):186-187.



188



BLM (Bloom) Mounira Amor-Guéret

Institut Curie - Section de Recherche, UMR 2027 CNRS, Batiment 110, Centre Universitaire, F-91405 Orsay Cedex, France (MAG)

Published in Atlas Database: September 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/BLM109.html DOI: 10.4267/2042/37665

This article is an update of : Amor-Guéret M. BLM (Bloom). Atlas Genet Cytogenet Oncol Haematol 2000;4(4):218 Huret JL. BLM (Bloom). Atlas Genet Cytogenet Oncol Haematol 1998;2(1):8 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Location: 15q26.1

DNA/RNA Transcription 4.4kb mRNA.

Protein Description 1417 amino acids; ATP binding in amino acid 689-696; DEAH box in 795-798; two putative nuclear localization signals in the C-term in 1334-1349.

Expression Accumulates to high levels in S phase of the cell cycle, persists in G2/M and sharply declines in G1. Hyperphoshorylated in mitosis.

Function 3'-5'DNA helicase; probable role in DNA replication and repair. Participates in a supercomplex of BRCA1-associated proteins named BASC (BRCA1-Associated genome Surveillance Complex). Recombinant protein promotes ATP-dependent branch migration of Holliday junctions.

Homology Homologous to RecQ helicases, a subfamily of DExH box-containing helicases; in particular, similarity with the four known human members in the RecQ subfamily, human RecQL, human Wrn, the product of

the Werner syndrome gene, and the recently identified human RecQL4, involved in the Rothmund-Thomson syndrome, and RecQL5 proteins.

Mutations Germinal Five BLM mutations introducing amino acid substitutions and four BLM mutations introducing premature nonsense codons into the coding sequence have been described to date; one BLM mutation consisting in a 6 bp deletion accompanied by a 7 bp insertion at nucleic acid position 2281 is common in patients from Ashkenazi Jewish ancestry, leading to a truncated protein of 739 amino acids in length; the mutated BLM protein is totally or partially retained in the cytoplasm, while the normal protein is nuclear.

Implicated in Bloom syndrome Disease Bloom syndrome is a chromosome instability syndrome/cancer prone disease (at risk of numerous, early occurring cancers of various types).

Prognosis 1/3 of patients are dead at mean age 24 years, and the mean age of the 2/3 remaining alive patients is 22 years.

Cytogenetics Chromatid/chromosome breaks; triradial and quadriradial figures, highly elevated spontaneous sister chromatid exchange rate.

BLM (Bloom) Amor-Guéret M


189

References Puranam KL, Blackshear PJ. Cloning and characterization of RECQL, a potential human homologue of the Escherichia coli DNA helicase RecQ. J Biol Chem. 1994 Nov 25;269(47):29838-45

Seki M, Miyazawa H, Tada S, Yanagisawa J, Yamaoka T, Hoshino S, Ozawa K, Eki T, Nogami M, Okumura K. Molecular cloning of cDNA encoding human DNA helicase Q1 which has homology to Escherichia coli Rec Q helicase and localization of the gene at chromosome 12p12. Nucleic Acids Res. 1994 Nov 11;22(22):4566-73

Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995 Nov 17;83(4):655-66

Ellis NA, German J. Molecular genetics of Bloom's syndrome. Hum Mol Genet. 1996;5 Spec No:1457-63

Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258-62

Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guéret M. Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome. Hum Mol Genet. 1997 Sep;6(9):1427-34

Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N. BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53

Karow JK, Chakraverty RK, Hickson ID. The Bloom's syndrome gene product is a 3'-5' DNA helicase. J Biol Chem. 1997 Dec 5;272(49):30611-4

Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto A. Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics. 1998 Dec 15;54(3):443-52

Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guéret M. Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome. Hum Mutat. 2000 Jun;15(6):584-5

Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guéret M. Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase. Oncogene. 2000 May 25;19(23):2731-8

Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The Bloom's syndrome gene product promotes branch migration of holliday junctions. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6504-8

Lindor NM, Furuichi Y, Kitao S, Shimamoto A, Arndt C, Jalal S. Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am J Med Genet. 2000 Jan 31;90(3):223-8

Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000 Apr 15;14(8):927-39


Amor-Guéret M. BLM (Bloom). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):188-189.



190



TAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/TAF2NID256.html DOI: 10.4267/2042/37666


Identity Other names: TAFIIN; TAF2N (TATA box binding protein (TBP)-associated factor, RNA polymerase II, N); RBP56 (RNA binding protein 56); TAFII68

HGNC (Hugo): TAF15

Location: 17q11.1-q11.2

DNA/RNA Description Spans 37kb; 16 exons.

Transcription 2.2 bp mRNA; alternative splicing: two isoforms of cDNAs consisting of 2144 and 2153 bp; coding sequence 1778 bp.

Protein Description 589 and 592 amino acid, 62 kDa ; comprises a N-term ser, tyr, gln, gly -rich region, followed by a an RNA binding domain and a Cys2/Cys2 finger motif, and repeats in C-term.

Expression Wide; in the fetus and in the adult.


Function Single strand DNA/RNA binding protein; part of theTFIID and RNA polymerase II complex of proteins which assemble on the promoter to form a pre-initiation

complex (PIC); TFIID is composed of a TATA-box-binding protein (TBP) and a number of TBP-associated factors (TAFIIS); contribute to the activation of transcription.

Homology With EWSR1 and FUS.

Mutations Somatic Overexpression of TAF2N-FLI-1 chimeras in NIH3T3 cells leads to oncogenic transformation.

Implicated in Extraskeletal myxoid chondrosarcomas with t(9;17)(q22;q11) --> 5 prime TAF2N/3 prime TEC Disease A rare tumour: 2.3% of soft tissue sarcomas often localized in deep soft tissues of the lower extremities.

References Reese JC, Apone L, Walker SS, Griffin LA, Green MR. Yeast TAFIIS in a multisubunit complex required for activated transcription. Nature. 1994 Oct 6;371(6497):523-7

Morohoshi F, Arai K, Takahashi EI, Tanigami A, Ohki M. Cloning and mapping of a human RBP56 gene encoding a putative RNA binding protein similar to FUS/TLS and EWS proteins. Genomics. 1996 Nov 15;38(1):51-7

Morohoshi F, Ootsuka Y, Arai K, Ichikawa H, Mitani S, Munakata N, Ohki M. Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes. Gene. 1998 Oct 23;221(2):191-8

TAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa) Huret JL


191

Bertolotti A, Bell B, Tora L. The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties. Oncogene. 1999 Dec 23;18(56):8000-10

Panagopoulos I, Mencinger M, Dietrich CU, Bjerkehagen B, Saeter G, Mertens F, Mandahl N, Heim S. Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11). Oncogene. 1999 Dec 9;18(52):7594-8

Sjögren H, Meis-Kindblom J, Kindblom LG, Aman P, Stenman G. Fusion of the EWS-related gene TAF2N to TEC in

extraskeletal myxoid chondrosarcoma. Cancer Res. 1999 Oct 15;59(20):5064-7

Green MR. TBP-associated factors (TAFIIs): multiple, selective transcriptional mediators in common complexes. Trends Biochem Sci. 2000 Feb;25(2):59-63


Huret JL. TAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):190-191.



192



PRDX1 (peroxiredoxin 1) Maité P Prosperi, Didier Ferbus, Gérard Goubin

Laboratoire d'Oncogenese, UMR147 CNRS, Section de recherche, Institut Curie, Paris, France (MPP, DF, GG)

Published in Atlas Database: October 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/PAGID266.html DOI: 10.4267/2042/37668


Identity Other names: PRX1

Location: 1p34.1 (pseudogene 9p22)

DNA/RNA Description 6 exons, 13 kb.

Protein Expression In proliferating tissues.

Localisation Cytosolic.

Function Unknown, overexpressed following induction of proliferation and oxidative stress.

Homology Thioperoxyredoxines.

References Prospéri MT, Ferbus D, Karczinski I, Goubin G. A human cDNA corresponding to a gene overexpressed during cell proliferation encodes a product sharing homology with amoebic and bacterial proteins. J Biol Chem. 1993 May 25;268(15):11050-6

Prospéri MT, Apiou F, Dutrillaux B, Goubin G. Organization and chromosomal assignment of two human PAG gene loci: PAGA encoding a functional gene and PAGB a processed pseudogene. Genomics. 1994 Jan 15;19(2):236-41


Prosperi MP, Ferbus D, Goubin G. PRDX1 (peroxiredoxin 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):192.



193



PML (Promyelocytic leukemia) Franck Viguié

Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex 04, France (FV)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PMLID41.html DOI: 10.4267/2042/37669


Identity Other names: MYL (myelocytic leukemia)

HGNC (Hugo): PML

Location: 15q24

Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description 9 coding exons; total gene sequence: 35 kb ?

Transcription 3 main mRNAs 4.6, 3.0 and 2.1 kb; alternative splicing generates at least 16 isoforms of mRNAs, varying in the region coding for the C-terminal part of the protein.

Protein Description 560 amino acids, 70 KDa (longest isoform); composed successively, from the N- to the C-terminus, by: 1- a proline-rich N-terminus 2- a so-called "tripartite motif", cysteine-histidine rich, composed of a RING finger structure and 2 B box domains, with putative DNA-binding function 3- a coiled-coil motif corresponding to a dimerization interface 4- a basic sequence with a nuclear localization domain, and 5- a serine-proline

rich C-terminal region, of unknown function, variable in length (alternative splicing) and containing phosphorylation sites. Expression In a wide variety of tissues. In hematopoietic tissue, expression apparently restricted to myeloid precursors.

Localisation Nuclear, as part of a multiproteic complex located into multiple subnuclear PML oncogenic domains (PODs).

Function Unknown to date; putative transcription factor; in conjunction with other proteins included in the PODs, it would play a role as tumor suppressor and in apoptosis.

Homology With (numerous) other RING finger/B box proteins.

Implicated in t(15;17)(q22;q21) / acute promyelocytic leukemia (APL) --> PML-RARA Disease Typical APL (or M3 ANLL, FAB classification), approximately 98% of APL cases; abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy.

Prognosis Immediate prognosis impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA plus chemotherapy.

PML (Promyelocytic leukemia) Viguié F


194

Cytogenetics Variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21.

Hybrid/Mutated gene The crucial fusion transcript is 5'PML-3'RARA, encoded by der(15) chromosome; the counterpart 5'RARA-3'PML encoded by der(17) is inconstant. Breakpoint in RARA gene is always located in intron between A and B domains. Three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARAtranscripts; V form would be linked to ATRA decreased sensitivity and S form to association with an excess of secondary chromosome changes.

Abnormal protein 106 Kda fusion protein; role in the leukemogenic process by probable interference with the signalling pathway leading to differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes involved in myeloid differentiation).

References de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558-61

Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663-74

Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM. Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. Cancer Res. 1992 Jul 1;52(13):3687-92

Chen Z, Tong JH, Dong S, Zhu J, Wang ZY, Chen SJ. Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia. Genes Chromosomes Cancer. 1996 Mar;15(3):147-56

Casini T, Grignani F, Pelicci PG. Genetics of APL and the molecular basis of retinoic acid treatment. Int J Cancer. 1997 Feb 7;70(4):473-4

Hodges M, Tissot C, Howe K, Grimwade D, Freemont PS. Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies. Am J Hum Genet. 1998 Aug;63(2):297-304

Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol. 1999 Sep;106(3):591-613

Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999 May 15;93(10):3167-215

Zhong S, Salomoni P, Pandolfi PP. The transcriptional role of PML and the nuclear body. Nat Cell Biol. 2000 May;2(5):E85-90


Viguié F. PML (Promyelocytic leukemia). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):193-194.



195



RARA (Retinoic acid receptor, alpha) Franck Viguié

Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex 04, France (FV)


Online updated version : http://AtlasGeneticsOncology.org/Genes/RARAID46.html DOI: 10.4267/2042/37670


Identity HGNC (Hugo): RARA

Location: 17q12

c-RARA (17q21) in normal cells: PAC 833D9 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description 9 exons; total gene sequence: 7450 bp.

Transcription 2.8 and 3.6 kb transcripts.

Protein Description 462 amino acids - 5 functional domains A/B (transcriptional regulation), C (DNA binding domain, contains 2 zinc fingers), D (cellular localization signal), E (ligand-binding domain) and F (function?).

Expression In hematopoietic cells.


Function Ligand-dependent transcription factor specifically involved in hematopoietic cells differentiation and maturation = receptor for all-trans retinoic acid (ATRA) and 9-cis RA which are intracellular metabolites of vitamine A, active in cellular differentiation and morphogenesis. After linking with ATRA, RARA binds with a high affinity as a heterodimer with RXR (retinoid X receptor protein) to the RARE domain (retinoic acid response elements), a DNA sequence common to a number of genes and located in their promoter. The gene response to RARA binding is modulated by a series of co-repressors and co-activators.

Homology with RARB and RARG (retinoic acid receptors beta and gamma), 9-cis RA receptors (RXRs) and receptors for thyroid and steroid hormones and for vitamine D3.

Implicated in t(15;17)(q22;q12) / acute promyelocytic leukemia (APL) -->PML - RARA Disease Typical APL (or M3 ANLL, FAB classification), approximately 98% of APL cases; abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy.

Prognosis Immediate prognosis impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA plus chemotherapy.

RARA (Retinoic acid receptor, alpha) Viguié F


196

Cytogenetics Variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21.

Hybrid/Mutated gene The crucial fusion transcript is 5'PML-3'RARA, encoded by der(15) chromosome; the counterpart 5'RARA-3'PML encoded by der(17) is inconstant. Breakpoint in RARA gene is always located in intron between A and B domains. Three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARAtranscripts; V form would be linked to ATRA decreased sensitivity and S form to association with an excess of secondary chromosome changes.

Abnormal protein 106 Kda fusion protein; role in the leukemogenic process by probable interference with the signalling pathway leading to differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes involved in myeloid differentiation).

t(11;17)(q23;q12) / acute promyelocytic leukemia -->PLZF-RARA Disease Variant acute promyelocytic leukemia (APL) form with atypical cytologic aspects (intermediate morphology between M2 and M3, no Auer rods) and no response to ATRA therapy; less than 1% of APL cases.

t(5;17)(q35;q12) / acute promyelocytic leukemia --> NPM-RARA Disease Exceptional; probable response to ATRA.

t(11;17)(q13;q12) / acute promyelocytic leukemia --> NuMA-RARA Disease Exceptional: probable response to ATRA.

t(11;17)(q23;q12) / M5 acute non lymphocytic leukemia --> MLL-RARA Disease 1 case to date; not to be confused with the t(11;17)(q23;q12) mentioned above; not found in APL; belongs to the MLL/11q23 leukemias.

References de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558-61

Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663-74

Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM. Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. Cancer Res. 1992 Jul 1;52(13):3687-92

Casini T, Grignani F, Pelicci PG. Genetics of APL and the molecular basis of retinoic acid treatment. Int J Cancer. 1997 Feb 7;70(4):473-4

Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol. 1999 Sep;106(3):591-613

Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999 May 15;93(10):3167-215


Viguié F. RARA (Retinoic acid receptor, alpha). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):195-196.



197



ZNF146 (zinc finger protein 146) Gérard Goubin

Laboratoire d'Oncogenèse, UMR147 CNRS, Section de recherche, Institut Curie, Paris, France (GG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/OZFID267.html DOI: 10.4267/2042/37667


Identity Other names: OZF

HGNC (Hugo): ZNF146

Location: 19q13.1

Protein Description 33 kDa; a kruppel zinc finger protein consisting of 10 zinc finger motives, preceeded by 10 amino acids and followed by 2 amino acids.

Expression In most proliferating tissues.

Localisation Nucleus.

Function Represse gene expression through a consensus motive.

Implicated in Disease Tumors of the exocrine pancreas.

Cytogenetics Amplification of the 19q13.1 region in a subset of pancreatic tumors.

References Le Chalony C, Prospéri MT, Haluza R, Apiou F, Dutrillaux B, Goubin G. The OZF gene encodes a protein consisting essentially of zinc finger motifs. J Mol Biol. 1994 Feb 18;236(2):399-404


Goubin G. ZNF146 (zinc finger protein 146). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):197.

Leukaemia Section Short Communication


198



Fibrogenesis imperfecta ossium Daniel Bontoux, Michel Alcalay, Jean-Loup Huret

Service de Rhumatologie, Centre Hospitalier Universitaire, 86021 Poitiers, France (DB, MA); Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/FibrogImperfOsID1190.html DOI: 10.4267/2042/37671


Clinics and pathology

X-rays of the cervical, thoracic, and lumbar spine (from left to right), and of the pelvic girdle (bottom) showing a marked demineralization with paucity of coarse, essentially vertical, trabeculae.

Fibrogenesis imperfecta ossium Bontoux D et al.


199

Disease Disorder of bone mineralization with abnormal bone collagen morphology often associated with monoclonal gammopathy; may well be a clinical variant of multiple myeloma.

Etiology Presents as an acquired metabolic bone disease of unknown aetiology; may also be a genetic disorder (at least in some cases), since a father and his daugther were affected.

Epidemiology 25 cases diagnosed to date; onset of symptoms mostly in 50-60 yr-old patients.

Clinics A combination of progressive and incapacitating bone pain and spontaneous, multiple fractures typically localized at tendon insertion sites; leads to extreme bone fragility, progressive immobility and usually results in the patient becoming bedridden. Serum alkaline phosphatase can be raised; monoclonal gammopathy is found in 25% of cases; 10 to 20% atypical plasma cells can be found in the bone marrow; however, evolution towards myeloma has never been reported. No other organ involvement has yet been reported. Diagnosis on bone biopsy showing the collagen defect.

Pathology Mimics osteomalacia with abnormal bone mineralization but there is complete loss of the birefringence characteristic of oriented collagen fibers; at ultrastructural level the normal lamellar pattern of collagen fibers is replaced by curved and extremely variable in thickness collagen fibrils.

Treatment Treatment with melphalan and corticosteroids over years has been successful in a number (but not all) of cases.

Prognosis Median survival is about 3 yrs.

Genetics Note Genes involved in the cases possibly inherited, if any, are unknown; genes involved in the plasma cells proliferation are also unknown.

References Baker SL, Turnbull HM. Two cases of a hitherto undescribed disease characterized by a gross defect in the collagen of the bone matrix. J Pathol Bacteriol. 1950;62:132-4.

BAKER SL. Fibrogenesis imperfecta ossium; a generalised disease of bone characterised by defective formation of the collagen fibres of the bone matrix. J Bone Joint Surg Br. 1956 Feb;38-B(1):378-417

Baker SL, Dent CE, Friedman M, Watson L. Fibrogenesis imperfecta ossium. J Bone Joint Surg Br. 1966 Nov;48(4):804-25

Thomas WC Jr, Moore TH. Fibrinogenesis imperfecta ossium. Trans Am Clin Climatol Assoc. 1969;80:54-62

Frame B, Frost HM, Pak CY, Reynolds W, Argen RJ. Fibrogenesis imperfecta ossium. A collagen defect causing osteomalacia. N Engl J Med. 1971 Sep 30;285(14):769-72

Golde D, Greipp P, Sanzenbacher L, Gralnick HR. Hematologic abnormalities in fibrogenesis imperfecta ossium. J Bone Joint Surg Am. 1971 Mar;53(2):365-70

Camus JP, Perie G, Brocheriou C, Crouzet J, Prier A, Cros F. [Fibrogenesis imperfecta ossium. Study of 2 cases in the same family]. Ann Med Interne (Paris). 1975 Aug-Sep;126(8-9):583-9

Swan CH, Shah K, Brewer DB, Cooke WT. Fibrogenesis imperfecta ossium. Q J Med. 1976 Apr;45(178):233-53

Christmann D, Wenger JJ, Dosch JC, Schraub M, Wackenheim A. [Axial osteomalacia. Comparative analysis with fibrogenesis imperfecta ossium (author's transl)]. J Radiol. 1981 Jan;62(1):37-41

Pinto F, Bonucci E, Mezzelani P, Cetta G, De Sandre G. Fibrogenesis imperfecta ossium (clinical, biochemical and ultrastructural investigations). Ital J Orthop Traumatol. 1981 Dec;7(3):371-85

Byron M, Woods CG. Fibrogenesis imperfecta ossium. Metab Bone Dis Rel Res. 1984;5:210-5.

Stoddart PG, Wickremaratchi T, Hollingworth P, Watt I. Fibrogenesis imperfecta ossium. Br J Radiol. 1984 Aug;57(680):744-51

Byers PD, Stamp TC, Stoker DJ. Case report 296. Fibrogenesis imperfecta. Skeletal Radiol. 1985;13(1):72-6

Stamp TC, Byers PD, Ali SY, Jenkins MV, Willoughby JM. Fibrogenesis imperfecta ossium: remission with melphalan. Lancet. 1985 Mar 9;1(8428):582-3

Lang R, Vignery AM, Jensen PS. Fibrogenesis imperfecta ossium with early onset: observations after 20 years of illness. Bone. 1986;7(4):237-46

Pombo FF, Arrojo Suarez de Centi L Verela Romero JR, Martin Egana R, Amal Monreal F. Fibrogenesis imperfecta ossium. Radiologia. 1987;29:469-72.

Ralphs JR, Stamp TC, Dopping-Hepenstal PJ, Ali SY. Ultrastructural features of the osteoid of patients with fibrogenesis imperfecta ossium. Bone. 1989;10(4):243-9

Carr AJ, Smith R, Athanasou N, Woods CG. Fibrogenesis imperfecta ossium. J Bone Joint Surg Br. 1995 Sep;77(5):820-9

Lafage-Proust M, Schaeverbeke T, Dehais J. Fibrogenesis imperfecta ossium: ineffectiveness of melphalan. Calcif Tissue Int. 1996 Oct;59(4):240-4

Wang CS, Steinbach LS, Campbell JB, Hayashi G, Yoon ST, Johnston JO. Fibrogenesis imperfecta ossium: imaging correlation in three new patients. Skeletal Radiol. 1999 Jul;28(7):390-5


Bontoux D, Alcalay M, Huret JL. Fibrogenesis imperfecta ossium. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):198-199.

Leukaemia Section Mini Review


200



Chronic myelogenous leukaemia (CML) Ali G Turhan

Translational Research - Cell Therapy, Laboratory, Institut Gustave Roussy, INSERM U. 362, 1 - 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France (AGT)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/CML.html DOI: 10.4267/2042/37672

This article is an update of: Huret JL. Chronic myelogenous leukaemia (CML). Atlas Genet Cytogenet Oncol Haematol.1997;1(2):89-91. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease CML is a malignant chronic myeloproliferative disorder (MPD) of the hematopoietic stem cell.

Phenotype/cell stem origin Evidence exists for the involvement of the most primitive and quiescent hematopoietic stem cell compartiment (CD34+/CD38-, Thy1+): t(9;22) is found in myeloid progenitor and in B-lymphocytes progenitors, but, involvement of the T-cell lineage is extremely rare.

Epidemiology Annual incidence: 10/106 (from 1/106 in childhood to 30/106 after 60 years); median age: 30-60 years; sex ratio: 1.2M/1F.

Clinics Splenomegaly; chronic phase (lasts about 3 years) with maintained cell's normal activities, followed by accelerated phase(s) (blasts still 30%; blood data: WBC:100 X 109/l and more during chronic phase, with basophilia; a few blasts; thrombocytosis may be present; low leucocyte alkaline phosphatases; typical acute leukaemia (AL) blood data at the time of myeloid or lymphoid-type blast crisis.

Cytology Hyperplastic bone marrow; granulocytes proliferation, with maturation; followed by typical AL cytology (see: t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL).

Treatment alphaIFN therapy or allogeneic bone marrow transplantation (BMT), donor leukocytes infusions.

Prognosis Median survival: 4 years with conventional therapy (hydroxyurea, busulfan), 6 years with aIFN therapy; allogeneic bone marrow transplantation may cure the patient; otherwise, the best treatment to date associates interferon a, hydroxyurea and cytarabine.

Cytogenetics Cytogenetics morphological All CML have a t(9;22), at least at the molecular level (see below); but not all t(9;22) are found in CML: this translocation may also be seen in ALL, and in ANLL (see: t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL), and the same genes are involved in the three diseases; in CML, the chromosomal anomaly persists during remission, in contrast with AL cases.

Cytogenetics molecular Is a useful tool for diagnostic ascertainment in the case of a 'masked Philadelphia' chromosome, where chromosomes 9 and 22 all appear to be normal, but where cryptic insertion of 3' ABL within a chromosome 22 can be demonstrated.

Additional anomalies 1- May be present at diagnosis (in 10%, possibly with unfavourable significance), or may appear during course of the disease, they do not indicate the imminence of a blast crisis, although these additional anomalies also emerge frequently at the time of acute transformation; 2- These are: +der(22), +8, i(17q), +19, most often, but also: +21, -Y, -7, -17, +17; acute transformation can also be accompanied with t(3;21)(q26;q22) (1% of cases); near haploidy can occur; of note, although rare,

Chronic myelogenous leukaemia (CML) Turhan AG


201

is the occurrence of chromosome anomalies which are typical of a given BC phenotype (e.g. t(15;17) in a promyelocytic transformation, dic(9;12) in a CD10+ lymphoblastic BC...); +8, +19, +21, and i(17q) occur more often in myeloid -rather than lymphoid- blast crises and apparent t(V;22) or t(9;V), where V is a variable.

Variants Chromosome, are found in 5-10% of cases; however, 9q34-3'ABL always joins 22q11-5'BCR in true CML; the third chromosome and breakpoint is, at times, not random. In a way, masked Philadelphia chromosomes (see above) are also variants.

Genes involved and proteins ABL Location 9q34

DNA/RNA Alternate splicing (1a and 1b) in 5'.

Protein Giving rise to 2 proteins of 145 kDa; contains SH (SRC homology) domains; N-term SH3 and SH2 - SH1 (tyrosine kinase) - DNA binding motif - actin binding domain C-term; widely expressed; localisation is mainly nuclear; inhibits cell growth.

BCR Location 22q11

DNA/RNA Various splicings.

Protein Main form: 160 kDa; N-term Serine-Treonine kinase domain, SH2 binding, and C-term domain which functions as a GTPase activating protein for p21rac; widely expressed; cytoplasmic localisation; protein kinase; probable role in signal transduction.

Result of the chromosomal anomaly Hybrid gene Description 1- The crucial event lies on der(22), id est 5' BCR/3' ABL hybrid gene is pathogenic, while ABL/BCR may or may not be expressed; 2- Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2; 3- Breakpoint in BCR is in a narrow region, therefore called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called

b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4.

Transcript 8.5 kb mRNA, resulting in a 210 kDa chimeric protein.

Detection RT-PCR for minimal residual disease detection.

Fusion protein Description P210 with the first 902 or 927 amino acids from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear. It is now clearly established that BCR-ABL is the oncogene responsible for the occurrence of CML. The hybrid protein has an increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated.

Oncogenesis A- Major molecular pathways activated by BCR-ABL. 1- BCR/ABL activates RAS signaling through the GRB2 adaptor molecule which interacts specifically with the Y177 of BCR. 2- PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated with secondary activation of the AKT/PKB pathway. 3- Integrity of transcription machinery induced by MYC is necessary for the transforming action of BCR-ABL. 4- More recently, activation of STAT (Signal transducers and activators of transcription) molecules has been described as a major molecular signaling event induced by BCR-ABL, with activation of essentially STAT5, 1, and 6. 5- Activation of the molecules of the focal adhesion complex (PAXILLIN, FAK) by BCR-ABL requires the role of the adaptor molecule CRK-L. 6- BCR-ABL activates negative regulatory molecules such as PTP1B and Abi-1 and their inactivation could be associated with progression into blast crisis. B- Correlations between molecular pathways and leukemic phenotype observed in primary CML cells or in BCR-ABL-transduced cells are currently limited. 1- BCR-ABL has anti-apoptotic activity (PI63K/Akt/STAT5). 2- BCR/ABL induces cell adhesive and migratory abnormalities in vitro in the presence of fibronection or in transwell assays (Abnormal integrin signaling/FAK/CRK-L/Abnormal response to chemokine SDF-1). 3- BCR-ABL induces a dose-effect relationship in CML cells with increased BCR-ABL mRNA during progression into blast crisis, with induction of genetic instability.

Chronic myelogenous leukaemia (CML) Turhan AG


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4- Molecular events associated with blast crisis: P53 mutation, methylation of ABL promoter, telomere shortening, Abl-1 inactivation.

To be noted Note 1- Blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ALL or ANLL with t(9;22) and P210 BCR/ABL hybrid; 2- JCML (juvenile chronic myelogenous leukaemia) is not the juvenile form of chronic myelogenous leukaemia: there is no t(9;22) nor BCR/ABL hybrid in JCML, and clinical features (including a worse prognosis) are not similar to those found in CML; 3- so called BCR/ABL negative CML should not be called so! 4- P53 is altered in 1/3 of BC-CML cases. 5- Most recent developments: Evidence of telomere shortening in CML cells during progression into blast crisis.

References Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood. 1988 Jul;72(1):294-8

Huret JL. Complex translocations, simple variant translocations and Ph-negative cases in chronic myelogenous leukaemia. Hum Genet. 1990 Oct;85(6):565-8

Heisterkamp N, Groffen J. Molecular insights into the Philadelphia translocation. Hematol Pathol. 1991;5(1):1-10

Kurzrock R, Talpaz M. The molecular pathology of chronic myelogenous leukaemia. Br J Haematol. 1991 Oct;79 Suppl 1:34-7

Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood. 1991 Jul 1;78(1):205-11

Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic myelogenous leukemia: biology and therapy. Leukemia. 1993 Apr;7(4):653-8

Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem. 1994 Sep 16;269(37):22925-8

Enright H, McGlave PB. Chronic myelogenous leukemia. Curr Opin Hematol. 1995 Jul;2(4):293-9

Bazzoni G, Carlesso N, Griffin JD, Hemler ME. Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest. 1996 Jul 15;98(2):521-8

Ilaria RL Jr, Van Etten RA. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem. 1996 Dec 6;271(49):31704-10

Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto-oncogenes. Curr Opin Hematol. 1997 Jan;4(1):3-11

Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997 Jul 24;337(4):223-9

Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997 Oct 15;16(20):6151-61

Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet B, Turhan AG. BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line. Oncogene. 1998 Jan 29;16(4):489-96

Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Genes Dev. 1998 May 15;12(10):1415-24


LaMontagne KR Jr, Flint AJ, Franza BR Jr, Pandergast AM, Tonks NK. Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo. Mol Cell Biol. 1998 May;18(5):2965-75

Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ, Eaves AC, Lansdorp PM. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood. 2000 Mar 15;95(6):1883-90


Turhan AG. Chronic myelogenous leukaemia (CML). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):200-202.



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Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V) Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky

Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK (EM)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/HairyCellID2036.html DOI: 10.4267/2042/37673


Clinics and pathology Phenotype/cell stem origin Cells from hairy cell leukemia (HCL) and hairy cell leukemia variant (HCL-V) have a distinct immunophenotype which is of a mature but not terminally differentiated activated B-cell. Although some similarities exist between these two conditions like the expression of B-cell activation marker CD103, CD11c and IgG heavy chain expression, differences exists between these two diseases. HCL is positive for CD25 (anti IL2 receptor) and HC2 while HCL-V is negative for CD25 and HC2.

Epidemiology First described as leukaemic reticulo endotheliosis, HCL predominantly affects middle aged males (male /female ratio = 4) while male predominance is not observed in HCL-V but they are older.

Clinics HCL patients present with splenomegaly, cytopenia(s) and variable proportions of circulating hairy cells. Monocytopenia is constant, lymphadenopathy is rare and the bone marrow is "dry tap" in most cases. HCL-V patients show most of the above features but have high white blood cell counts normal numbers of monocytes and aspirable bone marrow.

Cytology The typical hairy cell is large in size, has an eccentric and sometimes kidney shaped nucleus and abundant cytoplasm with long villi which is associated with alterations in the cytoskeletal architecture. HCL-V has a central round nucleus, a prominent nucleolus,

cytoplasmic villi and is intermediate in morphology between HCL and B-prolymphocytic leukaemia. HCL cells show strong acid phosphatase reaction which is resistant to tartaric acid.

Pathology The bone marrow and spleen histology is identical in HCL and HCL-V. The bone marrow shows a distinct pattern of interstital infiltration by lymphoid cells with spaces among them ('fried egg' pattern). Reticulin is invariably increased in HCL but not in HCL-V. Spleen histology shows expansion and infiltration of the red pulp with naked white pulp.

Treatment Interferon alpha produces good partial responses in HCL but invariably the disease relapses. The purine analogs 2 deoxycorformycin and 2-deoxyadenosine induce responses in >95% of patients, most of them complete and durable. HCL-V is not responsive to the above treatments with only half achieving transient partial responses to the purine analogs with splenectomy being the best palliative therapeutic measure.

Evolution HCL and HCL-V are characterised by a chronic clinical course with the symptoms deriving from cytopenias, and abdominal distension due to splenomegaly. Few patients undergo transformation.

Prognosis HCL has a good prognosis .In a large series 80% of patients survived at 12 years. HCL -V has a poorer prognosis and in the only largest series reported the median survival is 9 years.

Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V) Brito-Babapulle V et al.


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Cytogenetics Cytogenetics morphological Several reports describe nonclonal or oligoclonal abnormalities in HCL and in some with clonal abnormalities translocations involving the 14q32.3 the site of the IGH locus, rearrangements of 14q22-24 and abnormalities of chromosomes 11 and 12 have been described. One study reported a 40% incidence of chromosome 5 abnormalities. HCL-V is often characterised by a complex karyotype. Translocation t(14;18)(q32;q21) observed in follicular lymphoma and t(2;8)(p12;q24) observed in variant Burkitt lymphoma have been reported in HCL-V.

Cytogenetics molecular Deletion of the p53 tumour suppressor gene mapping to chromosome 17p13 occurs with a high incidence in both HCL and HCL-V. But a significant difference is observed in the proportion of cells with a deleted allele in HCL-V compared to HCL (P<0.01) and correlates with the well known tendency for transformation and poor response to therapy characteristic of HCL-V.

Genes involved and proteins Note Molecular studies suggest that hairy cells have aberrations in the constant region of the IgM intron which could be responsible for errors in class switching and explain the pattern of Ig heavy chain expression in HCL which does not fit the the class switching model which occurs in normal B-cell differentiation. Over expression of the BCL-1 gene on chromosome 11q13 and encoding Cyclin D-1 has been demonstrated by Northern blot for RNA and Western blot and immunocytochemistry for protein expression in over 70% of patients with HCL investigated (including 1HCL-V), but with no evidence for chromosomal or molecular rearrangement of the BCL-1 locus. The steady state m-RNA and protein levels of the leucocyte specific gene pp52 coding for a cytoskeletal protein and binding to filamentous actin (F-actin) is elevated in HCL.The gene maps to chromosome 11p15.5. Colocalisation of pp52 with F-actin occurs at the base of the villi. Interferon alpha (IFN alpha) a highly effective agent in the treatment of HCL has been shown to reduce pp52 m- RNA and blunt the villi.

References Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: a clinical review based on 71 cases. Ann Intern Med. 1978 Nov;89(5 Pt 1):677-83

Brito-Babapulle V, Pittman S, Melo JV, Parreira L, Catovsky D. The 14q+ marker in hairy cell leukaemia. A cytogenetic study of 15 cases. Leuk Res. 1986;10(2):131-8

Sainati L, Matutes E, Mulligan S, de Oliveira MP, Rani S, Lampert IA, Catovsky D. A variant form of hairy cell leukemia resistant to alpha-interferon: clinical and phenotypic characteristics of 17 patients. Blood. 1990 Jul 1;76(1):157-62

May W, Korenberg JR, Chen XN, Lunsford L, Wood WJ, Thompson A, Wall R, Denny CT. Human lymphocyte-specific pp52 gene is a member of a highly conserved dispersed family. Genomics. 1993 Mar;15(3):515-20

Brito-Babapulle V, Matutes E, Oscier D, Mould S, Catovsky D. Chromosome abnormalities in hairy cell leukaemia variant. Genes Chromosomes Cancer. 1994 Jul;10(3):197-202

Haglund U, Juliusson G, Stellan B, Gahrton G. Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions. Blood. 1994 May 1;83(9):2637-45

Kayano H, Dyer MJ, Zani VJ, Laffan MA, Matutes E, Asou N, Katayama I, Catovsky D. Aberrant rearrangements within the immunoglobulin heavy chain locus in hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:41-7

Matutes E, Morilla R, Owusu-Ankomah K, Houliham A, Meeus P, Catovsky D. The immunophenotype of hairy cell leukemia (HCL). Proposal for a scoring system to distinguish HCL from B-cell disorders with hairy or villous lymphocytes. Leuk Lymphoma. 1994;14 Suppl 1:57-61

Bosch F, Campo E, Jares P, Pittaluga S, Muñoz J, Nayach I, Piris MA, Dewolf-Peeters C, Jaffe ES, Rozman C. Increased expression of the PRAD-1/CCND1 gene in hairy cell leukaemia. Br J Haematol. 1995 Dec;91(4):1025-30

de Boer CJ, Kluin-Nelemans JC, Dreef E, Kester MG, Kluin PM, Schuuring E, van Krieken JH. Involvement of the CCND1 gene in hairy cell leukemia. Ann Oncol. 1996 Mar;7(3):251-6

Fleckenstein E, Dirks W, Dehmel U, Drexler HG. Cloning and characterization of the human tartrate-resistant acid phosphatase (TRAP) gene. Leukemia. 1996 Apr;10(4):637-43

Miyoshi E, Wall R, Thompson AA. Aberrant Expression of leucocyte specific pp52 in hairy cell leukemia (Meeting abstract ). Pros-Annu-Meer A-M Assoc Cancer Research.1996; 37: A325.

Wong KF, Kwong YL, Hui PK. Hairy cell leukemia variant with t(2;8)(p12;q24) abnormality. Cancer Genet Cytogenet. 1997 Oct 15;98(2):102-5

Vallianatou K, Brito-Babapulle V, Matutes E, Atkinson S, Catovsky D. p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant. Leuk Res. 1999 Nov;23(11):1041-5

Tallman MS and Polliack A Eds. . Hairy cell leukemia. Advances in Blood Disorders. Harwood academic publishers 2000.

Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D. The natural history and clinico-pathological features of the variant form of hairy cell leukemia. Leukemia. 2001 Jan;15(1):184-6


Brito-Babapulle V, Matutes E, Catovsky D. Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCL-V). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):203-204.



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t(9;22)(q34;q11) in CML Ali G Turhan

Translational Research - Cell Therapy, Laboratory, Institut Gustave Roussy, INSERM U. 362, 1 - 39, rue Camille Desmoulins, 94805 Villejuif, France (AGT)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0922CML.html DOI: 10.4267/2042/37674

This article is an update of: Huret JL. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol.1997;1(2):98-100. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Note Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this translocation may be seen in the following diseases: chronic myelogenous leukemia (CML), acute non lymphocytic leukemia (ANLL), and acute lymphocytic leukemia (ALL), and will therefore be described in the 3 different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL, t(9;22)(q34;q11) in CML is herein described.

t(9;22)(q34;q11) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and

Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain Vanderhaegen); diagram and breakpoints (Editor).

t(9;22)(q34;q11) in CML Turhan AG


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Clinics and pathology Disease CML: all CML have a t(9;22), at least at the molecular level (see below); but not all t(9;22) are found in CML, as already noted.

Phenotype/cell stem origin Evidence exists for the involvement of the most primitive and quiescent hematopoietic stem cell compartiment (CD34+/CD38-, Thy1+): t(9;22) is found in myeloid progenitor and in B-lymphocytes progenitors, but, involvement of the T-cell lineage is extremely rare.

Epidemiology Annual incidence: 10/106 (from 1/106 in childhood to 30/106 after 60 yrs); median age: 30-60 yrs; sex ratio: 1.2M/1F.

Clinics Splenomegaly; chronic phase (lasts about 3 yrs) with maintained cell's normal activities, followed by accelerated phase(s) (blasts still < 15%), and blast crisis (BC-CML) with blast cells > 30%; blood data: WBC: 100 X 109/l and more during chronic phase, with basophilia; a few blasts; thrombocytosis may be present; low leucocyte alkaline phosphatases; typical acute leukaemia (AL) blood data at the time of myeloid or lymphoid -type blast crisis.

Cytology Hyperplastic bone marrow; granulocytes proliferation, with maturation; followed by typical AL cytology (see t(9;22)(q34;q11)/ANLL, and t(9;22)(q34;q11)/ALL).

Treatment aIFN therapy or allogeneic bone marrow transplantation (BMT), donor leukocytes infusions.

Prognosis Median survival: 4 yrs with conventional therapy (hydroxyurea, busulfan), 6 yrs with aIFN therapy; allogeneic bone marrow transplantation may cure the patient; otherwise, the best treatment to date associates interferon a, hydroxyurea and cytarabine.

Cytogenetics Cytogenetics morphological The chromosomal anomaly persists during remission, in contrast with acute leukemia (AL) cases.

Cytogenetics molecular Is a useful tool for diagnostic ascertainment in the case of a 'masked Philadelphia' chromosome, where chromosomes 9 and 22 all appear to be normal, but where cryptic insertion of 3' ABL within a chromosome 22 can be demonstrated.

Additional anomalies 1. May be present at diagnosis (in 10%, possibly with unfavourable significance), or may appear during course of the disease, they do not indicate the imminence of a blast crisis, although these additional anomalies also emerge frequently at the time of acute transformation; 2. These are: +der(22), +8, i(17q), +19, most often, but also: +21, -Y, -7, -17, +17; acute transformation can also be accompanied with t(3;21) (q26;q22) (1% of cases); near haploidy can occur; of note, although rare, is the occurrence of chromosome anomalies which are typical of a given BC phenotype (e.g. t(15;17) in a promyelocytic transformation, dic(9;12) in a CD10+ lymphoblastic BC ...); +8, +19, +21, and i(17q) occur more often in myeloid -rather than lymphoid- blast crises.

Variants t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, are found in 5-10% of cases; however, 9q34-3'ABL always joins 22q11-5'BCR in true CML; the third chromosome and breakpoint is, at times, not random. In a way, masked Philadelphia chromosomes (see above) are also variants.

835J22 + 1132H12 and 72M14 Cohybridization of (835J22 +

1132H12; ABL) and 72M14 (BCR) on a CML patient carrying the t(9;22) translocation. Note the splitting of (835J22 + 1132H12) (red signal) and the colocalization on Ph chromosome (Ph) -

Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Genes involved and proteins ABL Location 9q34

DNA/RNA Alternate splicing (1a and 1b) in 5'.

Protein Giving rise to 2 proteins of 145 kDa; contains SH (SRC homology) domains; N-term SH3 and SH2 - SH1



207

(tyrosine kinase) - DNA binding motif - actin binding domain C-term; widely expressed; localisation is mainly nuclear; inhibits cell growth.

BCR Location 22q11

DNA/RNA Various splicing.

Protein Main form: 160 KDa; N-term Serine-Treonine kinase domain, SH2 binding, and C-term domain which functions as a GTPase activating protein for p21rac; widely expressed; cytoplasmic localisation; protein kinase; probable role in signal transduction.

Result of the chromosomal anomaly Hybrid gene Description 1. The crucial event lies on der(22), id est 5' BCR/3' ABL hybrid gene is pathogenic, while ABL/BCR may or may not be expressed; 2. Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2; 3. Breakpoint in BCR is in a narrow region, therefore called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4.

Transcript 8.5 kb mRNA, resulting in a 210 KDa chimeric protein.

Detection RT-PCR for minimal residual disease detection.

Fusion protein Description P210 with the first 902 or 927 amino acids from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear. It is now clearly established that BCR-ABL is the oncogene responsible for the occurrence of CML. The hybrid protein has an increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated.

Oncogenesis A- Major molecular pathways activated by BCR-ABL.

1. BCR/ABL activates RAS signaling through the GRB2 adaptor molecule which interacts specifically with the Y177 of BCR. 2. PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated with secondary activation of the AKT/PKB pathway. 3. Integrity of transcription machinery induced by MYC is necessary for the transforming action of BCR-ABL. 4. More recently, activation of STAT (Signal transducers and activators of transcription) molecules has been described as a major molecular signaling event induced by BCR-ABL, with activation of essentially STAT5, 1, and 6. 5. Activation of the molecules of the focal adhesion complex (PAXILLIN, FAK) by BCR-ABL requires the role of the adaptor molecule CRK-L. 6. BCR-ABL activates negative regulatory molecules such as PTP1B and Abi-1 and their inactivation could be associated with progression into blast crisis. B- Correlations between molecular pathways and leukemic phenotype observed in primary CML cells or in BCR-ABL-transduced cells are currently limited. 1. BCR-ABL has anti-apoptotic activity (PI63K/Akt/STAT5). 2. BCR/ABL induces cell adhesive and migratory abnormalities in vitro in the presence of fibronection or in transwell assays (Abnormal integrin signaling/FAK/CRK-L/Abnormal response to chemokine SDF-1). 3. BCR-ABL induces a dose-effect relationship in CML cells with increased BCR-ABL mRNA during progression into blast crisis, with induction of genetic instability. 4. Molecular events associated with blast crisis: P53 mutation, methylation of ABL promoter, telomere shortening, Abi-1 inactivation.

To be noted Note 1. Blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ALL or ANLL with t(9;22) and P210 BCR/ABL hybrid; 2. JCML (juvenile chronic myelogenous leukaemia) is not the juvenile form of chronic myelogenous leukaemia: there is no t(9;22) nor BCR/ABL hybrid in JCML, and clinical features (including a worse prognosis) are not similar to those found in CML; 3. so called BCR/ABL negative CML should not be called so! 4. P53 is altered in 1/3 of BC-CML cases 5. Most recent developments: Evidence of telomere shortening in CML cells during progression into blast crisis.



208

References Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood. 1988 Jul;72(1):294-8

Huret JL. Complex translocations, simple variant translocations and Ph-negative cases in chronic myelogenous leukaemia. Hum Genet. 1990 Oct;85(6):565-8

Heisterkamp N, Groffen J. Molecular insights into the Philadelphia translocation. Hematol Pathol. 1991;5(1):1-10

Kurzrock R, Talpaz M. The molecular pathology of chronic myelogenous leukaemia. Br J Haematol. 1991 Oct;79 Suppl 1:34-7

Martiat P, Michaux JL, Rodhain J. Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood. 1991 Jul 1;78(1):205-11

Gale RP, Grosveld G, Canaani E, Goldman JM. Chronic myelogenous leukemia: biology and therapy. Leukemia. 1993 Apr;7(4):653-8

Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem. 1994 Sep 16;269(37):22925-8

Enright H, McGlave PB. Chronic myelogenous leukemia. Curr Opin Hematol. 1995 Jul;2(4):293-9

Bazzoni G, Carlesso N, Griffin JD, Hemler ME. Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest. 1996 Jul 15;98(2):521-8

Ilaria RL Jr, Van Etten RA. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem. 1996 Dec 6;271(49):31704-10

Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto-oncogenes. Curr Opin Hematol. 1997 Jan;4(1):3-11

Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997 Jul 24;337(4):223-9

Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997 Oct 15;16(20):6151-61

Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet B, Turhan AG. BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line. Oncogene. 1998 Jan 29;16(4):489-96


LaMontagne KR Jr, Flint AJ, Franza BR Jr, Pandergast AM, Tonks NK. Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo. Mol Cell Biol. 1998 May;18(5):2965-75

Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ, Eaves AC, Lansdorp PM. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood. 2000 Mar 15;95(6):1883-90


Turhan AG. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):205-208.

Solid Tumour Section Mini Review


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Thyroid: Papillary carcinoma Marco A Pierotti

Istituto Nazionale dei Tumori, Dept. of Experimental Oncology, Via Venezian, 1 20133 Milan, Italy (MAP)


Online updated version : http://AtlasGeneticsOncology.org/Tumors/PapilThyroidCarID5053.html DOI: 10.4267/2042/37675


Classification Note Papillary Thyroid Carcinomas (PTCs) derives from the thyroid follicular cells, as the other type of well-differentiated thyroid carcinomas, the follicular ones; however these differentiated thyroid cancers are regarded as different entities: The follicular carcinoma, solitary and encapsulated, is associated with endemic goiter, a diet with low iodine intake and metastatizes almost exclusively via the blood stream, often to bones. The papillary carcinoma, on the contrary, is multifocal and associated with a previous radiation exposure, high iodine intake and metastatizes through lymphatic spread to regional lymph-nodes.

Cytogenetics Cytogenetics Morphological Seventy cases of papillary thyroid carcinomas (PTCs) have been reviewed, 51 of them displaying a normal karyotype (73%). In 10 cases non recurrent structural

or numerical changes were observed. In particular, 9 cases showed recurrent structural changes including: inv10(q11.2q21.2) in 5 tumors, a t(10;17)(q11.2;q23) in two cases, and a der(1) in the last two tumors.

Genes involved and proteins Note These abnormalities represent the cytogenetic mechanisms which activate the receptor tyrosine kinase (RTK) proto-oncogenes RET on chromosome 10 and NTRK1 on chromosome 1, respectively. The alternative involvement of the RET and NTRK1 tyrosine kinases receptors in the development of a consistent fraction (45%) of PTCs has been demonstrated. Somatic rearrangements, both intra and interchromosomal, of RET and NTRK1 produce several forms of oncogenes. In all cases, RET or NTRK1 tyrosine kinase (TK) domains are fused to the amino-terminus of different gene products. The latter have been defined as 'activating' genes.

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RET Location 10q11.2

Protein The RET proto-oncogene codes for the tyrosine kinase receptor of GDNF (Glial cell Derived Neurotrophic Factor) and Neurturin (NTN); activation of RET by GDNF or NTN has been shown to require one of two accessory proteins, GDNFRa and GDNFRb.

Germinal mutations Germline mutations of proto-RET result in human diseases including familial medullary thyroid carcinoma MTC, multiple endocrine neoplasia type 2A and 2B (MEN2A and MEN2B) and Hirschsprung’s disease.

Somatic mutations RET is expressed in the thyroid by normal C cells and their pathologic counterpart, medullary thyroid carcinoma (MTC); moreover, RET expression can be detected in normal adrenal medulla and pheochromocytomas.

H4/D10S170 Location 10q21

AKAP10 (subunit RI-a of Protein Kinase A) Location 17q23

ELE1 Location 10q11

NTRK1 Location 1q22

DNA / RNA The NTRK1 proto-oncogene encodes the high affinity receptor for Nerve Growth Factor (NGF).

Protein NTRK1 is primarily expressed in the nervous system.

Germinal mutations Mice carrying a germline mutation that eliminates NTRK1 show severe sensory and sympathetic neuropathies, including the loss of neurons of the dorsal root ganglia associated with nociceptive functions, and most die within one month of birth; interestingly, point mutations leading to the inactivation of the NTRK1 receptor, have been identified in patient with CIPA (Congenital Insensitivity to Pain with Anhidrosis), an autosomal-recessive disorder characterized by absence of reaction to noxious stimuli; thus NGF signalling via NTRK1

appears essential for the development and maintenance of both the peripheral and central nervous systems.

TPM3 Location 1q22-23

TPR Location 1q25

TFG Location 3q12

Result of the chromosomal anomaly Hybrid Gene Note The RET/PTC1 oncogene, represents the first example of oncogene activation in solid tumors due to an acquired chromosomal abnormality.

Description RET/PTC1 is a chimeric transforming sequence generated by the fusion of the TK domain of RET to the 5' terminal sequence of the gene H4/D10S170; both partners in the fusion have been localized to chromosome 10q and their fusion is the molecular event consequent to a paracentromeric inversion of chromosome 10q, inv 10 (q11.2q21.2).

Fusion Protein Oncogenesis H4/D10S170 has been shown to display a coiled-coil sequence which confers to the oncoprotein the ability to form dimers, resulting in a constitutive activation of the TK function.

Hybrid Gene Note A second example of RET activation is the RET/PTC2 oncogene; the cytogenetic analysis of one case of RET/PTC2 positive carcinoma revealed that this oncogene arises from a t(10;17)(q11.2;q23) reciprocal translocation.

Description In this case the rearrangement involved the gene of the regulatory subunit RI-a of Protein Kinase A, which maps to chromosome 17q23.

Fusion Protein Oncogenesis Interestingly, like the H4 gene, RI-a also contains a dimerization domain and the construction of RET/PTC2 mutants with deletions in RI-a, has demonstrated that the formation of dimers is necessary to express the activity of the oncogene.

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Hybrid Gene Note Finally, a third example of RET activation in PTCs has been reported, RET/PTC3; also in this case, a paracentric inversion of the long arm of chromosome 10 was identified.

Fusion Protein Oncogenesis In this oncogene, the TK domain of RET is fused to sequences derived from a previously unknown gene named ELE1 (otherwise named RFG). ELE1 is localized in the same chromosomal region of RET, 10q11.2.

Hybrid Gene Note Several cases of PTCs showed an activation of the NTRK1 proto-oncogene; in three specimens a chimeric sequence generated by the rearrangement of an isoform of non-muscle tropomyosin (TPM3) and NTRK1 was identified; the former has been mapped to chromosome 1q22-23; therefore, the NTRK1 localization on 1q22 suggested that a 1q intrachromosomal rearrangement could have generated the TRK oncogene.

Description Molecular analysis of TRK positive PTCs revealed the presence, not only of the product of the oncogenic rearrangement (5'TPM3-3'NTRK1), but also of that related to the reciprocal event (5'NTRK1-3'TPM3); this finding indicates that an intrachromosomal inversion, inv(1q), provided the mechanism of the NTRK1 oncogenic activation in these tumors.

Note In the remaining cases genes different from TPM provided the 5' terminus of the oncogene; therefore the latter were designated as TRK-T. Three cases showed the fusion of NTRK1-TK domain to sequences of the TPR (Translocated Promoter Region) gene, originally identified as part of the MET oncogene.

Description The first of these cases, TRK-T1, is encoded by a hybrid mRNA containing 598 nucleotides of TPR and 1148 nucleotides of NTRK1; the TPR locus is on chromosome 1q25; therefore, as for TRK, an intrachromosomal rearrangement, molecularly defined as an inversion of 1q, is responsible for its formation; a

rearrangement involving the same two genes, TPR and NTRK1, has been found in two other papillary thyroid tumors; although the two rearrangements involve different genomic regions of the partner genes, they occur in the same intron of both TPR and NTRK1; as a consequence, the same mRNA and 1323 aminoacid oncoprotein are produced and designated TRK-T2 in both cases; similarly to TRK-T1, the molecular characterization of these rearrangements indicated the chromosomal mechanism leading to the oncogenic activation as an inv(1q).

Note As for the last two oncogenes derived from NTRK1 activation, one is still uncharacterized whereas the other, designated TRK-T3, has recently been analyzed.

Description Sequence analysis revealed that TRK-T3 contains 1412 nucleotides of NTRK1 preceded by 598 nucleotides belonging to a novel gene named TFG (TRK Fused Gene) encoding a 68 kDa cytoplasmic protein; the latter displays, in the TFG part, a coiled-coil region that endows the oncoprotein with the capability to form complexes, as shown by the TK domains; in this condition, the latter can recruit SH2 and SH3 containing cytoplasmic effector proteins.

To be noted Note In fact Ret/ptcs oncoproteins and in some cases Trk oncoproteins were demonstrated to bind and activate PLCg, an SH2-containing enzyme catalyzing the hydrolisis of phosphatydilinositol biphospate to inositol trophoshate and diacyl glicerol, and Shc, an adaptor protein belonging to the Ras pathway; the relocalization in the cytoplasm of RET and NTRK1 enzymatic activity could allow their interaction with unusual substrata, perhaps modifying their functional properties.

References Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology. 2007 Mar;148(3):936-41


Pierotti MA. Thyroid: Papillary carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):209-211.

Solid Tumour Section Review


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Bladder: transitional cell carcinoma Jean-Loup Huret, Claude Léonard

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH), Cytogenetique, Laboratoire d'Anatomo Pathologie, CHU Bicetre, 78 r Leclerc, F94270 Le Kremlin-Bicetre, France (CL)


Online updated version : http://AtlasGeneticsOncology.org/Tumors/blad5001.html DOI: 10.4267/2042/37676

This article is an update of: Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.1999;3(4):205-206. Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Bladder cancer: gross pathology: the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre

Bedossa.

Classification Note Existence of different histologic types: Transitional cell carcinoma of the bladder, herein described, Squamous cell carcinoma, Adenocarcinoma (2%), rare, Poorly differenciated carcinoma/small cell carcinoma, exceptional.

Clinics and pathology Disease Cancer of the urothelium.

Epidemiology Transitional cell carcinoma is the most frequent bladder cancer in Europe and in the USA, representing 90-95% of cases, while squamous cell carcinoma represents

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only 5% in these countries, but up to 70-80% of cases in the Middle East. Annual incidence: 250/106, 2% of cancers, the fourth cancer in males, the seventh in females, 3M/1F. Occurs mainly in the 6th-8th decades of life. Risk factors: cigarette smoking and occupational exposure (aniline, benzidine, naphtylamine); 20 to 30 years latency after exposure.

Clinics Hematuria, irritation.

Pathology Grading and staging: tumours are: Graded by the degree of cellular atypia (G0->G3), and Staged: - pTIS carcinoma in situ (but high grade), and - pTa papillary carcinoma, both mucosally confined; - pT1 lamina propria invasive; - pT2 infiltrates the superficial muscle, and - pT3a, the deep mucle; - pT3b invasion into perivesical fat; - pT4 extends into neighbouring structures and organs.

Treatment Resection (more or less extensive: electrofulguration --> cystectomy); chemo and/or radiotherapy, BCG-therapy.

Evolution Recurrence is highly frequent.

Prognosis According to the stage and the grade; pTa is of good prognosis (> 90% are cured); prognosis is uncertain in pT1 and G2 tumours, where cytogenetic findings may be relevant prognostic indicators. 20% survival at 1 year (stable at 3 years) is found in T4 cases; however, identification of individual patient's prognosis is often difficult, although of major concern for treatment decision and for follow up.

Cytogenetics Cytogenetics Morphological Highly complex: pseudo diploid karyotypes with only a few abnormalities in early stages, evolving towards pseudo-tetraploides hyper complexes karyotypes with numerous unrecognizable markers in advanced stages; pseudo-octoploidy may arise; the most frequent anomaies are: +7, -9, -11 or del(11p), del(13q), del(17p), and rearrangements of chromosomes 1, 5, and 10; monosomy 9 is a very early event, that may even appear at the dysplastic stage; we will use indifferently the terms deletion and loss of heterozygocity (LOH) for chromosome regions, and preferably LOH for genes. Chromosome 1: implicated in 35% of cases; mainly del(1p); 1p22 and 1q31 are the most frequently involved; amplification 1p32 has been noted; P73 (1p36) is often over-expressed.

Chromosome 3: implicated in 30%, mostly in complex karyotypes; amplifications 3p21-24, 3q24 have been found; del(3p) is associated with high grade/stage. Chromosome 4: deletions in 20%, in particular in 4p16 and 4q13-23; amplification of 4q26 has been noted. Chromosome 5: i(5p) occurs in 35% of cases. Chromosome 6: del(6q) in 25%; may be correlated with tumour invasion. Chromosome 7: trisomy 7 is frequent in this cancer, as well as in many other cancers, but also in normal tissues; may still be of bad prognostic significance. Chromosome 8: del(8p) in 25%; deletion of 8p12-pter, 8p22 in particular, may be associated with high grade/stage; gains of 8q (especially 8q23-qter) may be associated with tumour progression; however, C-MYC (8q24) is rarely amplified. Chromosome 9: monosomy 9 or deletions of chromosome 9 are found in about 50% of cases; at times found as the sole anomaly, demonstrating that it is an early event, found equally in PTa stage and in more advanced stages; not associated with a given grade, and not correlated with P53 expression; it has, however, recently been hypothezised that monosomy 9 could indicate a risk of recurrence; LOH appear to be numerous within a given chromosome (e.g. LOH in 9p21, 9q22, 9q31-32, 9q33 and 9q34), but loci remain to be precised, as reports are controversial; homozygous deletions of CDKN2A/MTS1/P16 (9p21) have been documented; LOH + mutation on the second allele of CDKN2A are rare, but of significance; CDKN2A is implicated in Pta stage but not in PTIS, where P53 is found mutated; CDKN2B/INK4B/P15 (9p21) is also implicated in a small subset of cases; PAX5 (9p13) may be over-expressed in tumours; GSN (9q34) has a very low expression in tumours in comparison with its expression in normal bladder; LOH + mutation on the second allele of TSC1 (9q33-34) has recently been described. Chromosome 10: del(10)(q23-25) has been noted; PTEN (10q23), appears to be implicated in a very few percentage of cases (homozygote deletion has been found); Fas/APO1/CD95 (10q24): loss of one allele and mutation in the second allele has been reported; a hot-spot of mutations has been determined; amplification 10q13-14 has been found. Chromosome 11: monosomy 11 or del(11p) is found in 20 to 50% of cases, more often in high grade and invasive tumours, associated with tumour progression, often found at the time of tetraploidisation; LOH in 11p15.1-p15.5; HRAS1 (11p15.5) is mutated in 15% of cases; amplifications of 11q13-22 have been noted, but would not be a prognostic factor. Chromosome 12: del(12q) in 20%; amplification of 12q13-15 and/or 12q15-24 may be found. Chromosome 13: del(13q) is found in 25% of cases; correlated with high grade/stage; an altered Rb (13q14) is expressed in 30 to 40% of tumours; these are high



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stage, invasive, and indicate a short survival; 90% of tumours expressing Rb are invasives; disregulation of the normal P16-Rb interactions have been documented, with hyper expression of Rb and loss of function of P16; amplification in 13q21-31 has been noted. Chromosome 14: del(14q) in 25% of cases (especially 14q12 and 14q32); may be associated with tumour progression. Chromosome 17: del(17p) in 40% of cases; LOH are mainly in 17p12-13, 17q11-22, and 17q 24-25; del(17p) is a late event, mainly found in pT2 to pT4; also found in a subset of pTIS, which might be a relevant prognostic indicator for these tumours; P53 (17p13) alterations are correlated with grade and stage (often PT3), and tumour progression; P53 is mutated in more than 50% of high grade/stage tumours, and in most PTIS; P53 is a prognostic factor: by high grade/stage tumours, those expressing P53 are of a worse prognosis; by low grade/stage, those not expressing P53 are of better outcome; there is usually LOH + mutation on the second allele of P53; ERBB2/P185 (17q21) is expressed in high grade/stages tumours, in metastases, and is associated with relapses; NF1 (17q11) expression may be very low in tumours; amplification of 17q22-23 has been noted. Chromosome 18: del(18q) in 25%; associated with high grade/stage; amplifications of 18q11 and 18q22 have been found. Chromosome 22: amplification of 22q11-12 has been noted. Chromosome Y: Y loss in 30%; probably not associated with stage, grade, Ki67, or P53 expression. Other: double minute are found in high grades/stages; multifocal tumours exhibit genomic instability; this genomic instability is already present in normal tissus and is increased in tumour tissus from the same specimens, suggesting that a general genetic instability is a reason for multifocality.

Cytogenetics Molecular Flow cytometry for DNA index measurement has been used in the past, but comparative genomic hybridization (CGH) is now a major tool for deletions and duplications determination; multi-FISH (M-FISH) sould be very useful in early-stage cases (with pseudo-diploid karyotypes) to determine structural rearrangements.

Genes involved and proteins Note The process 1- is multistep, 2- can take major and minor routes, still to be determined; genes involved in transitional cell carcinoma of the bladder are therefore numerous and most are still unknown; some are quoted above.

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Habuchi T, Yoshida O, Knowles MA. A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. Hum Mol Genet. 1997 Jun;6(6):913-9

Richter J, Jiang F, Görög JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997 Jul 15;57(14):2860-4

Wagner U, Bubendorf L, Gasser TC, Moch H, Görög JP, Richter J, Mihatsch MJ, Waldman FM, Sauter G. Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer. Am J Pathol. 1997 Sep;151(3):753-9

Bartlett JM, Watters AD, Ballantyne SA, Going JJ, Grigor KM, Cooke TG. Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? Br J Cancer. 1998 Jun;77(12):2193-8

Baud E, Catilina P, Boiteux JP, Bignon YJ. Human bladder cancers and normal bladder mucosa present the same hot spot of heterozygous chromosome-9 deletion. Int J Cancer. 1998 Sep 11;77(6):821-4

Bruch J, Wöhr G, Hautmann R, Mattfeldt T, Brüderlein S, Möller P, Sauter S, Hameister H, Vogel W, Paiss T. Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified

interval on chromosome arm 8q. Genes Chromosomes Cancer. 1998 Oct;23(2):167-74

Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, Bose S, Wang SI, Parsons R, Sidransky D. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene. 1998 Jun 18;16(24):3215-8

Erbersdobler A, Friedrich MG, Schwaibold H, Henke RP, Huland H. Microsatellite alterations at chromosomes 9p, 13q, and 17p in nonmuscle-invasive transitional cell carcinomas of the urinary bladder. Oncol Res. 1998;10(8):415-20

Halachmi S, Madjar S, Moskovitz B, Nativ O.. Genetic alterations in bladder cancer. Cancer J 1998; 11: 86-88.

Hovey RM, Chu L, Balazs M, DeVries S, Moore D, Sauter G, Carroll PR, Waldman FM. Genetic alterations in primary bladder cancers and their metastases. Cancer Res. 1998 Aug 15;58(16):3555-60

Kavaler E, Landman J, Chang Y, Droller MJ, Liu BC. Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity. Cancer. 1998 Feb 15;82(4):708-14

Simon R, Bürger H, Brinkschmidt C, Böcker W, Hertle L, Terpe HJ. Chromosomal aberrations associated with invasion in papillary superficial bladder cancer. J Pathol. 1998 Aug;185(4):345-51

Tsutsumi M, Tsai YC, Gonzalgo ML, Nichols PW, Jones PA. Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer. Oncogene. 1998 Dec 10;17(23):3021-7

Aaltonen V, Boström PJ, Söderström KO, Hirvonen O, Tuukkanen J, Nurmi M, Laato M, Peltonen J. Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro. Am J Pathol. 1999 Mar;154(3):755-65

Adshead JM, Ogden CW, Penny MA, Stuart ET, Kessling AM. The expression of PAX5 in human transitional cell carcinoma of the bladder: relationship with de-differentiation. BJU Int. 1999 Jun;83(9):1039-44

Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer. 1999 May;80(5-6):904-8

Baud E, Catilina P, Bignon YJ. p16 involvement in primary bladder tumors: analysis of deletions and mutations. Int J Oncol. 1999 Mar;14(3):441-5

Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H, Czerniak B. Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene. 1999 Feb 4;18(5):1197-203

Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Cancer Res. 1999 Jun 15;59(12):2791-3

Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Roy JY, Luthra R, Logothetis C, Von Eschenbach AC, Grossman HB, Benedict WF, Batsakis JG. Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene. 1999 Feb 4;18(5):1185-96

Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE. Can p53 help select patients with invasive bladder cancer for bladder preservation? J Urol. 1999 Jan;161(1):20-2; discussion 22-3



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Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T, Knowles MA. Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene. 1999 Apr 22;18(16):2657-61

Junker K, Werner W, Mueller C, Ebert W, Schubert J, Claussen U. Interphase cytogenetic diagnosis of bladder cancer on cells from urine and bladder washing. Int J Oncol. 1999 Feb;14(2):309-13

Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK. Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet. 1999 Apr 15;110(2):87-93

Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK, Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ. Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res. 1999 Jul 1;59(13):3068-72

Mahdy E, Yoshihiro S, Zech L, Wester K, Pan Y, Busch C, Döhner H, Kallioniemi O, Bergerheim U, Malmström PU. Comparison of comparative genomic hybridization, fluorescence in situ hybridization and flow cytometry in urinary bladder cancer. Anticancer Res. 1999 Jan-Feb;19(1A):7-12

Neuhaus M, Wagner U, Schmid U, Ackermann D, Zellweger T, Maurer R, Alund G, Knönagel H, Rist M, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Polysomies but not Y chromosome losses have prognostic significance in pTa/pT1 urinary bladder cancer. Hum Pathol. 1999 Jan;30(1):81-6

Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M. Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22. Genes Chromosomes Cancer. 1999 May;25(1):1-5

Pycha A, Mian C, Hofbauer J, Brössner C, Haitel A, Wiener H, Marberger M. Multifocality of transitional cell carcinoma results from genetic instability of entire transitional epithelium. Urology. 1999 Jan;53(1):92-7

Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knönagel H, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res. 1999 Nov 15;59(22):5687-91

Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet Y. Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31. Oncogene. 1999 Jan 7;18(1):157-63

Stacey M, Matas N, Drake M, Payton M, Fakis G, Greenland J, Sim E. Arylamine N-acetyltransferase type 2 (NAT2), chromosome 8 aneuploidy, and identification of a novel NAT1 cosmid clone: an investigation in bladder cancer by interphase FISH. Genes Chromosomes Cancer. 1999 Aug;25(4):376-83

Thygesen P, Risch A, Stacey M, Fakis G, Giannoulis F, Takle L, Knowles M, Sim E. Genes for human arylamine N-acetyltransferases in relation to loss of the short arm of chromosome 8 in bladder cancer. Pharmacogenetics. 1999 Feb;9(1):1-8

Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito S, Smith DI, Liu W. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene. 1999 Feb 25;18(8):1629-33

Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res. 1999 Sep 15;59(18):4658-61

Awata S, Sakagami H, Tozawa K, Sasaki S, Ueda K, Kohri K. Aberration of chromosomes 8 and 11 in bladder cancer as detected by fluorescence in situ hybridization. Urol Res. 2000 Jun;28(3):185-90

Böhm M, Kleine-Besten R, Wieland I. Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas. Int J Cancer. 2000 Mar 20;89(2):194-7

Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm-Audorff U, Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M, T'Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer. 2000 Apr 15;86(2):289-94

Choi C, Kim MH, Juhng SW, Oh BR. Loss of heterozygosity at chromosome segments 8p22 and 8p11.2-21.1 in transitional-cell carcinoma of the urinary bladder. Int J Cancer. 2000 May 15;86(4):501-5

Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges S, Benedict WF. Genetic modeling of human urinary bladder carcinogenesis. Genes Chromosomes Cancer. 2000 Apr;27(4):392-402

Louhelainen J, Wijkström H, Hemminki K. Allelic losses demonstrate monoclonality of multifocal bladder tumors. Int J Cancer. 2000 Aug 15;87(4):522-7

Louhelainen J, Wijkström H, Hemminki K. Initiation-development modelling of allelic losses on chromosome 9 in multifocal bladder cancer. Eur J Cancer. 2000 Jul;36(11):1441-51

Muscheck M, Sükösd F, Pesti T, Kovacs G. High density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3. Lab Invest. 2000 Jul;80(7):1089-93

Salem C, Liang G, Tsai YC, Coulter J, Knowles MA, Feng AC, Groshen S, Nichols PW, Jones PA. Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res. 2000 May 1;60(9):2473-6


Huret JL, Léonard C. Bladder: transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):212-217.

Cancer Prone Disease Section Mini Review


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Bloom syndrome Mounira Amor-Guéret



Online updated version : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html DOI: 10.4267/2042/37677

This article is an update of: Huret JL. Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol.1998;2(2):65-66. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see

below) - JL Huret.

Inheritance Autosomal recessive; frequency is about 2/105 newborns in Ashkenazi Jews and in the Japanese (founder effect: affected persons descent from a common ancestor); much rarer otherwise.

Clinics Note 168 cases have been registered in the Bloom's syndrome Registry by James German; BS patients are

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predisposed to all types of cancer observed in the general population; thus, BS is a model of initiation and promotion of cancer, and highligths internal causes/processes of cancers.

Phenotype and clinics - Phenotypic spectrum variable; - Growth: dwarfism: intrauterine growth retardation; birth weight: below 2.3 kg; mean length: 44 cm; adult length < 145 cm; - Skin: hyperpigmented (café au lait) spots; hypopigmented areas; sun sensitive telangiectatic erythema; in butterfly configuration across the face: resembles lupus erythematous; - Head: microcephaly; dolichocephaly; narrow face; prominent nose and/or ears; characteristic high-pitched voice; - Normal intelligence; - Immune deficiency --> frequent infections (may be life-threatening); - Other: myocardopathy; hypogonadism in male patients; hypertriglyceridemia.

Neoplastic risk Nearly half of patients have had at least one cancer (10% of whom having had more than one primary cancer, which is quite characteristic of Bloom's); mean age at first cancer onset: 25 years (range: 2-49 years): Acute leukaemias (ALL and AML) in 15 % of cases; lymphomas in 15 % as well; these occur mainly before the thirties.

Carcinomas (of a wide variety) occur in 30 % of cases, mainly after the age of 20 years. Benign tumours (10%).

Evolution Major medical complications apart from cancers are: chronic lung disease, and diabetes mellitus (in 10 %).

Prognosis 1/3 of patients are dead at mean age 24 years (oldest died at 49 years, youngest died before 1 year), and the mean age of the 2/3 remaining alive patients is 22 years (range: 4-46 years).

Cytogenetics Inborn conditions Chromatid/chromosome breaks; triradial and quadriradial figures, in particular symetrical quadriradial configuration involving homologous chromosomes (Class I qr), which are pathognomonic and which may be due to a mitotic crossing-over. Diagnosis is on the (pathognomonic) highly elevated spontaneous sister chromatid exchange rate (90 SCE per cell; more than 10 times what is normally found); in some persons a minor population of low SCE cells exists, suggesting a recombination event between maternal and paternal alleles (with different mutations), giving rise to a wild type functional gene; this allowed to localize the gene in a very elegant strategy. Heterozygotes are not detectable by cytogenetic studies.

Sister chromatid exchange in a normal subject (left) and in a Bloom syndrome patient (right) - Mounira Amor-Guéret.

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Other findings Note Slowing of the cell cycle (lenthening of the G1 and S phases). Spontaneous mutation rate 10 times higher than normal cells.

Genes involved and proteins Note No complementation group.

BLM Location 15q26.1

Protein Description: 1417 amino acids; contains one ATP binding site, one DEAH box, and two putative nuclear localization signals. Expression: Accumulates to high levels in S phase of the cell cycle, persists in G2/M and sharply declines in G1; hyperphoshorylated in mitosis. Localisation: Nuclear. Function: 3-5 DNA helicase; probable role in DNA replication and repair. Participates in a supercomplex of BRCA1-associated proteins named BASC (BRCA1-Associated genome Surveillance Complex). Recombinant protein promotes ATP-dependent branch migration of Holliday junctions. Homology: Homology with the RecQ helicases.

Mutations Germinal: Five BLM mutations introducing amino acid substitutions and four BLM mutations introducing premature nonsense codons into the coding sequence have been described to date; one BLM mutation consisting in a 6 bp deletion accompanied by a 7 bp insertion at nucleic acid position 2281 is common in patients from Ashkenazi Jewish ancestry, leading to a truncated protein of 739 amino acids in length; the mutated BLM protein is totally or partially is retained in the cytoplasm, while the normal protein is nuclear.

References German J. Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients. Am J Hum Genet. 1969 Mar;21(2):196-227

Gorlin RJ, Cohen MM, Levin LS.. Syndromes of the head and neck. Oxford Monogr Med Genet. 1990; 19: 297-300.



Ellis NA, German J. Molecular genetics of Bloom's syndrome. Hum Mol Genet. 1996;5 Spec No:1457-63

Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guéret M. Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome. Hum Mol Genet. 1997 Sep;6(9):1427-34

German J. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet. 1997 Jan;93(1):100-6

Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N. BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53

Karow JK, Chakraverty RK, Hickson ID. The Bloom's syndrome gene product is a 3'-5' DNA helicase. J Biol Chem. 1997 Dec 5;272(49):30611-4

Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guéret M. Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome. Hum Mutat. 2000 Jun;15(6):584-5

Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guéret M. Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase. Oncogene. 2000 May 25;19(23):2731-8

Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The Bloom's syndrome gene product promotes branch migration of holliday junctions. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6504-8

Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000 Apr 15;14(8):927-39


Amor-Guéret M. Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):218-220.

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Simpson-Golabi-Behmel syndrome Hope H Punnett

Genetics Laboratory, St. Christopher's Hospital for Children, Erie Avenue at Front Street, Philadelphia, PA 19134, USA (HHP)


Online updated version : http://AtlasGeneticsOncology.org/Kprones/SimpsonGolabiID10038.html DOI: 10.4267/2042/37678


Identity Inheritance X-linked with heterogeneity; most families map Xq26; one large pedigree maps to Xp22.

Clinics Phenotype and clinics Pre-natal and post-natal overgrowth syndrome, similar to Beckwith-Wiedemann syndrome. Xq26: coarse facies with mandibular overgrowth, cleft palate, heart defects, hernias, supernumerary nipples, renal and skeletal abnormalities. Xp22: lethal form, multiple anomalies, hydrops fetalis, death within first 8 weeks of life with a neoplastic risk.

Neoplastic risk Wilms tumor, neuroblastoma during early childhood; one case of hepatocellular carcinoma reported.

Genes involved and proteins GPC3 Protein Description: GPC3, an X-linked recessive overgrowth gene, may encode a negative regulator of mesothelial cell growth, based on observation that down-regulation of GPC3 is a common occurrence in malignant mesothelioma. Function: Proteoglycans are essential cofactors in cell-cell recognition systems, cell-matrix adhesion processes and receptor-growth factor interactions.

References David G. Integral membrane heparan sulfate proteoglycans. FASEB J. 1993 Aug;7(11):1023-30

Hughes-Benzie RM, Pilia G, Xuan JY, Hunter AG, Chen E, Golabi M, Hurst JA, Kobori J, Marymee K, Pagon RA, Punnett HH, Schelley S, Tolmie JL, Wohlferd MM, Grossman T, Schlessinger D, MacKenzie AE. Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families. Am J Med Genet. 1996 Dec 11;66(2):227-34

Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet. 1996 Mar;12(3):241-7

Lapunzina P, Badia I, Galoppo C, De Matteo E, Silberman P, Tello A, Grichener J, Hughes-Benzie R. A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma. J Med Genet. 1998 Feb;35(2):153-6

Brzustowicz LM, Farrell S, Khan MB, Weksberg R. Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of Simpson-Golabi-Behmel syndrome. Am J Hum Genet. 1999 Sep;65(3):779-83

Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC, Jhanwar SC, Mossman BT, Filmus J, Testa JR. Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma. Oncogene. 2000 Jan 20;19(3):410-6

Paine-Saunders S, Viviano BL, Zupicich J, Skarnes WC, Saunders S. glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development. Dev Biol. 2000 Sep 1;225(1):179-87


Punnett HH. Simpson-Golabi-Behmel syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):221.



222



Cockayne syndrome Claude Viguié

Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CS)


Online updated version : http://AtlasGeneticsOncology.org/Kprones/CockayneID10015.html DOI: 10.4267/2042/37679


Identity Inheritance: Autosomal recessive.

Clinics Phenotype and clinics Normal newborn; growth failure from the age of six months; diagnosis from the age of two years on: Senile appearance of the skin (pigmentation, atrophy) with "mickey mouse" aspect (microcephaly, large ears, large nose, deep set eyes). "Senil dwarf" aspect in contrast with long limbs, large hands and feet, cold fingers with cyanosis, flexion contractures of joints. Sensitivity to sunlight. Severe encephalopathia with profond mental retardation and sensory disorders (deafness, optic atrophy). Pigmentary retinitis leading to cecity. Other disorders: hypertension, early atherosclerosis, intracranial calcification, glomerulosclerosis.

Neoplastic risk No increased susceptibility to skin tumors and other cancers, except for Cockayne syndrome expressing xeroderma pigmentosum (XP) symptoms (association with XPG, XPD or XPB group).

Evolution Clinical heterogeneity, but early death from cachexia and dementia, early cutaneous tumors and atherosclerosis.

Cytogenetics Inborn conditions As in XP, the UV ligth-induced level of sister chromatid exchange (SCE) is increased as well as the rate of chromosome aberrations, mainly chromatid breaks.

Genes involved and proteins Note There is genetic heterogeneity in CS, giving rise to complementation groups. The genes involved are: CSA, also called ERCC8 (ERCC for Excision-Repair Cross Complementing rodent repair deficiency) located on chromosome 5, CSB, also called ERCC6 , located in 10q11-21; outside CSA and CSB, there is: 3 patients who are XPB/CS, involving XPB, also called ERCC3, located in 2q21; 2 patients XPD/CS, involving XPD, also called ERCC2, located in 19q13; and 6 patients XPG/CS, involving XPG, also called ERCC5, located in 13q32 (note: the class of patients with both XP and CS were classified earlier as CS III, but not anymore).

References Brosh RM Jr, Balajee AS, Selzer RR, Sunesen M, Proietti De Santis L, Bohr VA. The ATPase domain but not the acidic region of Cockayne syndrome group B gene product is essential for DNA repair. Mol Biol Cell. 1999 Nov;10(11):3583-94

Bartenjev I, Butina MR, Potocnik M. Rare case of Cockayne syndrome with xeroderma pigmentosum. Acta Derm Venereol. 2000 May;80(3):213-4

de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis. 2000 Mar;21(3):453-60

Hanawalt PC. DNA repair. The bases for Cockayne syndrome. Nature. 2000 May 25;405(6785):415-6

Rockx DA, Mason R, van Hoffen A, Barton MC, Citterio E, Bregman DB, van Zeeland AA, Vrieling H, Mullenders LH. UV-induced inhibition of transcription involves repression of transcription initiation and phosphorylation of RNA polymerase II. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10503-8


Viguié C. Cockayne syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):222.

Cancer Prone Disease Section Short Communication


223



Trichothiodystrophy (TTD) Claude Viguié

Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CV)


Online updated version : http://AtlasGeneticsOncology.org/Kprones/TrichothioID10042.html DOI: 10.4267/2042/37680


Identity Alias: Ichtyosis, brittle hair, intellectual impairment, decreased fertility, and short stature syndrome (IBIDS)

Inheritance: Recessive autosomal.

Clinics Phenotype and clinics Photosensitivity, Ichtiosys, Brittle hair, Intellectual impairment, Decreased fertility, Short stature (PIBIDS syndrome). Photosensitivity is absent in 50% of cases (therefore called IBIDS syndrome).

Neoplastic risk This familial disease IS NOT a cancer prone disease but it involves the same complementation groups as in xeroderma pigmentosum and Cockayne syndrome (XPD, XPB), and share defects in similar genes.

Prognosis Depends on the DNA repair defect (photosensitivity: XPD-ERCC2, XPB-ERCC3, TTD-A) and on the transcription errors (other signs).

Cytogenetics Inborn conditions No known chromosome abnormalities.

Genes involved and proteins Note The DNA repair defect is found in 3 classes: Patient with TTD-A group (low level of the TFIIH transcription factor), Patients mutated in the XPB gene (TTD/XPB), involving XPB, also called ERCC3, located in 2q21; and All the other patients mutated in the XPD gene (TTD/XPD), involving XPD, also called ERCC2, located in 19q13.

References de Boer J, van Steeg H, Berg RJ, Garssen J, de Wit J, van Oostrum CT, Beems RB, van der Horst GT, van Kreijl CF, de Gruijl FR, Bootsma D, Hoeijmakers JH, Weeda G. Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. Cancer Res. 1999 Jul 15;59(14):3489-94



Viguié C. Trichothiodystrophy (TTD). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):223.



224



Werner syndrome Mounira Amor-Guéret



Online updated version : http://AtlasGeneticsOncology.org/Kprones/WernerID10017.html DOI: 10.4267/2042/37681


Identity Inheritance Autosomal recessive; prevalence of carriers is as high as 1 in 150 to 1 in 200; frequency is about 0.3/105 newborns in Japanese.

Clinics Note Uncommon disorder characterized by early onset of geriatric diseases and described as a "caricature of aging" or "progeria of adults".

Phenotype and clinics Early onset of atherosclerosis, osteoporosis, diabetes mellitus, scleroderma-like skin changes, especially in the extremities, cataract, graying of the hair, subcutaneous calcification, slender limbs, stocky trunk, beaked nose and cancers of non-epithelial cell origin.

Neoplastic risk Malignancy is found in approximately 10% of WRN patients. Excess of soft-tissue sarcomas, osteosarcomas, myeloid disorders and benign meningiomas. In addition, the Japanese have an excess of melanomas and follicular, and anaplastic thyroid carcinomas.

Evolution During the first decade of life, WS patients appear normal: the first manifestation is lack of the adolescent growth spurt. In the twenties, WS patients develop bilateral ocular cataract and premature graying of the hair. In the thirties and forties, osteoporosis, type II diabete mellitus, accelerated atherosclerosis, and cancer occur. In the fourth and fifth decades, WS patients often succumb to cardiovascular disease or cancer.

Cytogenetics Inborn conditions 'Variegated translocation mosaicism': skin fibroblast cell lines from WRN patients are usually composed of one or several clones, each marked by a distinctive, apparently balanced translocation.

Other findings Note WS cells express constitutively high levels of collagenase in vitro. WS cells exhibit a mutator phenotype characterized by extensive deletions: 8-fold higher average frequency of 6-thioguanine-resistant lymphocytes in Werner syndrome patients than in sex- and age-matched normal controls. WS cells usually achieve only about 20 population doublings versus approximately 60 in normal cells in culture (WRN gene could be a 'counting' gene controlling the number of times that human cells are able to divide before terminal differentiation). Forced expression of telomerase in Werner syndrome fibroblasts confers extended cellular life span and probable immortality.

Genes involved and proteins Complementation groups No complementation group.

WRN Location 8p12

Protein Description: 1432 amino acids; contains one ATP binding site, one DEXH helicase box, one exonuclease

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domain unique among known RecQ helicases in the N-terminal region, a nuclear localization signal in the C-terminus and a direct repeat of 27 amino acids between the exonuclease and helicase domains. Localisation: Nuclear, predominant nucleolar localization. Function: 3'-5' DNA helicase; 3'-5' exonuclease; functionally interacts with DNA polymerase delta (POLD1), which is required for DNA replication and DNA repair; functionally interacts with Ku, involved in double strand DNA break repair by non-homologous DNA end joining. Homology: With the RecQ helicases.

Mutations Germinal: All of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature termination: not a single missense mutation had been identified.

References Hoehn H, Bryant EM, Au K, Norwood TH, Boman H, Martin GM. Variegated translocation mosaicism in human skin fibroblast cultures. Cytogenet Cell Genet. 1975;15(5):282-98

Fukuchi K, Martin GM, Monnat RJ Jr. Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5893-7

Fukuchi K, Tanaka K, Kumahara Y, Marumo K, Pride MB, Martin GM, Monnat RJ Jr. Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients. Hum Genet. 1990 Feb;84(3):249-52

Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall S. The gene responsible for Werner syndrome may be a cell division "counting" gene. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12030-4

Thweatt R, Goldstein S. Werner syndrome and biological ageing: a molecular genetic hypothesis. Bioessays. 1993 Jun;15(6):421-6

Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S, Miki T, Nakura J, Ogihara T, Ells J, Smith M, Melaragno MI, Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz

A, Schellenberg GD, Martin GM. Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum Mol Genet. 1996 Dec;5(12):1909-13

Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258-62

Ogburn CE, Oshima J, Poot M, Chen R, Hunt KE, Gollahon KA, Rabinovitch PS, Martin GM. An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum Genet. 1997 Dec;101(2):121-5

Marciniak RA, Lombard DB, Johnson FB, Guarente L. Nucleolar localization of the Werner syndrome protein in human cells. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6887-92

Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW, Goto M. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. Cancer. 1999 Mar 15;85(6):1345-52

Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner syndrome. Hum Mutat. 1999;13(4):271-9

Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D, Bohr VA. Ku complex interacts with and stimulates the Werner protein. Genes Dev. 2000 Apr 15;14(8):907-12

Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA. Functional interaction between the Werner Syndrome protein and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4603-8

Li B, Comai L. Functional interaction between Ku and the werner syndrome protein in DNA end processing. J Biol Chem. 2000 Sep 15;275(37):28349-52

Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RG, Kipling D. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nat Genet. 2000 Jan;24(1):16-7


Amor-Guéret M. Werner syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):224-225.



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Xeroderma pigmentosum Claude Viguié

Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CV)


Online updated version : http://AtlasGeneticsOncology.org/Kprones/XerodermaID10004.html DOI: 10.4267/2042/37682


Identity Inheritance Recessive autosomal; occurrence is favored by consanguinity; frequency is 0.3/105 with large geographical variations; higher frequenciy observed in Tunisia (10/105, role of consanguinity) and in Japan (1/105); rare in black people.

Clinics Note Xeroderma pigmentosum (XP) is caused by a defect in nucleotide excision repair mechanisms; various clinical aspects and intensity of signs are described according to the gene involved (7 known complement groups) and type of mutation.

Phenotype and clinics Severe sun photosensitivity (poikilodermia): induced precocious cutaneous lesions, concomitant to first sun exposures, on the exposed areas (hands, arms, face); dry skin, senile-like, cutaneous retractions (premature aging of the skin). Photophobia, often the first sign, before cutaneous lesions; followed by bilateral cataract; increased risk of ocular benign and malign tumors. Neurological signs (14 to 40% of patients): mental retardation, pyramidal syndrome, peripheral neuropathia; more severe central nervous system (CNS) disorders are observed when mutations occur in XPA DNA binding site. Clinical heterogeneity: related to genetic heterogeneity of the disease (7 known complementation groups A, B,

C, D, E, F, G and 7 characterized genes). Intensity and precocity of signs are dependent on the gene involved; groups A, C, D and G are associated with a more severe disease. The same genes are implicated in two related diseases: Cockayne syndrome (groups B, D and G) and trichothiodystrophy (groups B and D).

Neoplastic risk Propensity to cutaneous tumors after sun exposure (risk X 1000 to develop cancer on sun -exposed areas of the skin): benign lesions, multiple basal cell carcinomas and spinal carcinomas (occuring in 2 to 40 year old patients, median age 8 yrs), malignant melanomas slightly later than carcinomas (risk x 2000 compared to normal population), rarely other skin tumors (fibrosarcomas, angiosarcomas). Propensity to various solid tumors (mainly brain tumors, x 10 to 20 fold in comparison with general population).

Treatment Photoprotection; genetic counseling; treatment of malignant tumors.

Evolution Progressively increasing number of cutaneous, ocular and other solid tumors; cutaneous atrophy with numerous scars and aesthetic damage; skin abnormalities comparable to what is clinically and histologically observed with aging; blindness; severe mental retardation.

Prognosis 2/3 death before adult age.

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Above: characteristic aspect of evolved lesions of the face in an XP patient. To be noted multiple scars of carcinomas and an aged aspect of the skin with poikilodermia. Below: multiple basocellular carcinomas on the face of an XP patient. Thick arrow points to a recent lesion, and thin arrow to a scar of an old lesion - Courtesy Daniel Wallach.

Cytogenetics Inborn conditions Hypermutability after UV irradiation in cell cultures; no increased of spontaneous chromosome abnormalities in lymphocytes of fribroblastes; however, after UV-exposure an increased number of sister chromatid exchanges (SCE) and chromosome aberrations are observed (mainly chromatid-type abnormalities); fibroblasts express an increased sensitivity to chemical mutagens; there is no cytogenetic feature useful for XP diagnosis.

Genes involved and proteins Note The clinical and cytologic XP heterogeneity is the consequence of the genetic heterogeneity: 7

complementation groups (XPA to G) plus an additional variant form, evidenced by somatic cell fusion experiments. The genes involved are: XPA, located in 9q22, XPB, also called ERCC3 (ERCC for Excision-Repair Cross Complementing rodent repair deficiency), located in 2q21, XPC, located in 3p25, XPD, also called ERCC2, located in 19q13, XPE, located on chromosome 11 XPF, also called ERCC4, located in 19q13 XPG, also called ERCC5, located in 13q32, and XPV, also called Pol eta, and located in 6p12-21. All XP genes are implicated in various steps of the NER (nucleotide excision repair) system, except the XP variant that is mutated in a mutagenic DNA polymerase (POL H) able to bypass the UV-induced DNA lesions; various alterations of the same gene may involve various phenotypes Cockayne syndrome , trichothiodystrophy).

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References Cleaver JE, Thompson LH, Richardson AS, States JC. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat. 1999;14(1):9-22

Riou L, Zeng L, Chevallier-Lagente O, Stary A, Nikaido O, Taïeb A, Weeda G, Mezzina M, Sarasin A. The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. Hum Mol Genet. 1999 Jun;8(6):1125-33

van Steeg H, Kraemer KH. Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol Med Today. 1999 Feb;5(2):86-94

Cleaver JE. Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum. J Dermatol Sci. 2000 May;23(1):1-11


Nakura J, Ye L, Morishima A, Kohara K, Miki T. Helicases and aging. Cell Mol Life Sci. 2000 May;57(5):716-30


Viguié C. Xeroderma pigmentosum. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):226-228.

Deep Insight Section


229



Micronuclei : Pitfalls and Problems John RK Savage

34 City Road, Tilehurst, Reading, RG31 5HB, UK (JRKS)

Published in Atlas Database: July 2000

Online updated version : http://AtlasGeneticsOncology.org/Deep/MicronucleiID20016.html DOI: 10.4267/2042/37683


Introduction Ionizing radiation and numerous chemical mutagens cause structural chromosomal aberrations, many of which are visible at the light-microscope level. There are many types, and a complicated classification (Savage, 1976), so that specialised knowledge and training are required for reliable scoring. These aberrations form the basis of a large amount of radiobiological and DNA-repair theory and have many practical uses in the fields of biological dosimetry, clinical cytogenetics and environmental monitoring (Heddle, 1990; Streffer et al., 1998). A proportion of the aberrations (usually referred to as "Asymmetrical events" or "Unstable aberrations" (Carrano and Heddle, 1973; Savage, 1976)) give rise to chromosome fragments without spindle attachment organelles (kinetochores, centromeres). These are termed "acentric fragments", (AF). When the cell divides, some of these fragments are excluded from the main daughter nuclei and form small extra nuclei within the cytoplasm, either on their own, or in conjunction with other fragments. Such "micronuclei" (MN) can appear in the cytoplasm of either, or both, daughter cells. Depending on the origin of the excluded fragment, i.e. the type of aberration from which it was derived, both, or only one daughter cell will suffer genetic loss. In some cases, the aberrations lead to mechanical separation problems ("bridges") at anaphase as well as fragment loss. These events will ultimately kill the cell, though "death" (measured by cessation of division) may not occur until 2-4 divisions have taken place. With time, therefore, when an acute radiation dose, or treatment with a very short-lived chemical clastogen has been given, MN production ultimately ceases, and

the frequency in new cells returns to the control (un-treated) level. It is logical to expect that there should be some numerical relationship between the number of AF per cell and the number of MN per cell derived from them. On the assumption that this relationship is fairly simple, MN scoring in interphase cells has been proposed, and used, as a quick and easy substitute for the more difficult and time-consuming metaphase aberration analysis (Countryman and Heddle, 1976; Heddle, 1973; Heddle, 1975; Muller and Streffer, 1994). In the context of mutagen screening, or when purely qualitative answers are required, this is to some extent valid, and meaningful results can be obtained (Heddle, 1990; Muller and Streffer, 1994). However, the MN system is full of pitfalls for the unwary and there are many factors which conspire to uncouple any simple relationship between AF and MN, making critical quantitative work very difficult. The purpose of this paper is to highlight some of the MN-system problems, because, to appreciate them, will help in the design of meaningful experiments and applications, and in the interpretation of any results obtained.

Factors which can influence the AF Æ MN relationship For convenience, I will group the factors that influence the observed frequencies of MN derived from a given frequency of AF under four broad headings:

- Production factors. - Fragment-fate factors. - Cell-kinetic factors. - The time-displacement factor. Production factors.

Micronuclei : Pitfalls and Problems Savage JRK


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Figure 1 :

a) Fragment origin. Following radiation, very few of the MN observed are derived from lagging whole chromosomes, most come from asymmetrical structural aberrations. In contrast, most of the spontaneously occurring ones appear to arise from whole chromosomes. This has been shown by the application of kinetochore-specific probes to micronuclei (Degrassi and Tanzarella, 1988; Fenech and Morley, 1989; Tucker and Eastmond, 1990). There is only one type of MN but many different kinds of aberration can contribute to them. Figure 1 summarises the principal types of aberration which produce AF. The principal structural chromosomal aberrations

which contribute acentric fragments (AF) to form micronuclei (MN). The diagram also indicates those which produce compound fragments, i.e. composed of segments from more than one chromosome/chromatid and also those which produce mechanical separation problems ("bridges") at anaphase. Fragment loss leads to genetic imbalance and ultimate cell death ; this may affect either one, or both daughter cells. Since there is frequently more than one aberration per cell, the probability of both daughters being affected is increased. Which kinds predominate will depend upon the kind of cells used, the stage of the cell in the cycle when exposed to the clastogen, and the clastogen used.



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Ionizing radiation can produce all the types of structural change, but the vast majority of chemical clastogens produce, primarily, only chromatid-types. Some of the fragments are compound, containing segments from more than one chromosome, others are simple. Thus, the extent of genetic loss varies considerably and may affect both daughters, or only one.

b) MN Generation. Only AF excluded from the daughter nuclei at telophase can produce MN. Thus, cell division is a necessary condition for their appearance, and the MN frequency will be expected to increase with time after treatment as more and more aberration-bearing cells pass through mitosis. Exposure of a non- or very slowly dividing cell population, or a treatment that inhibits cell division, will mean that almost no MN are observed. AF included in either daughter nucleus will duplicate along with the rest of the genome during S-phase and, if the cell divides again, will produce a second crop of MN, the duplication of the initial included fragment augmenting the observed frequency. As mentioned above, neither fragment loss nor mechanical separation problems at anaphase necessarily kill the cell immediately (though the latter usually precludes further divisions) so quite a few AF-bearing cells divide 2 or 3 times before cessation leading to a continuous, but eventually declining, production of MN for some time after treatment. In the majority of cell systems, both the absolute and the relative frequency of the various forms of primary aberrations vary as the cell transits the cycle. Consequently, the generation of excluded AF (and hence MN) will also fluctuate with time after treatment. In addition to this, we have to remember that with most clastogens, especially chemicals, a further crop of primary aberrations can arise in later divisions from unused long-lived lesions. These also will contribute AF for MN.

Fragment-fate factors. a) The Inclusion probability, (PI). The probability that an AF is included when the daughter nuclei re-form after division (Savage, 1988). The probability of exclusion, PE = (1.0 - PI). When PI <1.0, which appears to be the universal condition, then MN will form at successive divisions as outlined above. There is no recorded case of PI = 0. A number of pertinent questions need to be asked, and answered, about PI : Is it a constant ? In some cases the answer is "No". It differs between cell type within species (fibroblasts versus lymphocytes, (Savage, 1988)), and between different species for the same cell type. Good information is lacking on effects of cell age, of karyotype composition, of fragment-size or of fragment number.

Is it affected by the clastogen used ? Is it dependent upon the dose? There is some evidence that fragment exclusion falls as the dose of ionizing radiation increases. Finally, and importantly, is PI affected by any drug used to interfere with the cytoskeleton, and concomitant cytokinesis? As, for example, cytochalasin-B (Fenech and Morley, 1985; Fenech and Morley, 1986), which is now almost universally used to overcome the generation/dilution problem discussed below.

b) Sister-fragment separation. Chromosome-type (pre-replication) AF are always paired, whereas chromatid-type (post replication) AF are mixed, but predominantly single (Figure 1). It is assumed, especially for theoretical work, that all paired fragments retain their adherence, and are transmitted to MN as a unit pair (Braselmann et al., 1986; Carrano and Heddle, 1973; Wakata and Sasaki, 1987). Recent evidence from certain species indicates that this may not always be the case (Das and Sharma, 1987), so that in some systems, two MN may sometimes arise from one AF pair.

c) Fragment coalescence. As the number of AF per cell increases, so also does the probability that one MN may contain several AF. Cytoplasmic currents around the spindle apparatus can lead to vortexes ("Sargasso Seas") where AF collect, enhancing this probability. Thus, at higher clastogen doses, any 1:1 AF:MN expectation breaks down. Several authors have noted the paucity of multi-MN cells and the tendency to under-dispersion of MN between-cell distributions.

Cell-kinetic Factors. a) Dilution. "Once an MN, always an MN". For practical purposes, MN, once formed, do not disappear for a long time, even in cells that have lost the ability to divide. Nor, in the vast majority of cases, do MN themselves divide, although when present at mitosis, they occasionally show "premature chromosome condensation" (PCC). Since nearly all cells that carry AF have a limited life span (~1-4 divisions), only a finite number of MN are produced, and the cells that are carrying them will soon be out-grown by "normal", non-AF producing, non-MN bearing, cells which will progressively "dilute" the observed MN/cell frequency. This conflict between "generation" versus "dilution" with time after treatment leads to a "humped" yield-time curve, the profile of which is highly dose-dependent (Brock and Williams, 1985; Roberts et al., 1986). This means that often, there is no unique MN frequency that can be set against a given dose, with inevitable uncertainty in the shape of any dose-response curve. Consequently, since the rate of



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generation and of dilution are both affected by kinetic factors (see below), neither the peak frequency, nor the integrated area under the yield time curve, are reliable measures of damage. This is a problem all too familiar to those who attempt quantitative work with chromatid-type aberrations (Savage and Papworth, 1991).

b) Mitotic delay and perturbation. Every known clastogen disturbs the orderly progression of cells towards division. The magnitude of the effect is dose, time, and probably stage dependent. Obviously, the changed cell-rates and orders will have a pronounced effect on factors like "generation" and "dilution" and, by changing the mixture of cells present in the scored sample, this will affect the observed frequency of MN.

c) Interphase "death". The failure of a cell to reach the next mitosis after treatment. Sometimes loosely equated with "apoptosis", but this latter term should be reserved for the highly specialised "programmed" interphase death having certain well defined biomolecular characteristics. Interphase "death" as a general term, does not necessarily involve cessation of physiological activity, or nuclear degeneration (as an example consider the "feeder-layer" technique). Interphase "death" is a regular feature of chemical clastogens, and some cell types show it after ionizing radiation (e.g. unstimulated lymphocytes). If extensive, a severe reduction in MN production will result. The phenomenon may not be random, affecting only certain developmental phases, so some bias of the AF source may be introduced.

The Time-displacement Factor. This is probably the most frequently overlooked factor when quantitative comparisons between AF and MN are made (Savage, 1989). It is the failure to remember that aberration frequencies are determined at a point in time (usually after a short colcemid metaphase accumulation) and are therefore "instantaneous" mean frequencies. Observed frequencies of MN are, however, "running" means, based on the cumulative number of MN derived from all divisions antecedent to the time of sampling. Now, an instantaneous-mean and a running-mean are mathematically quite different things, and are not readily comparable. One of the dramatic differences is, that in sequential samples, significant fluctuations seen in the former, are thoroughly damped in the latter, and this effectively severs any meaningful relationship between AF and MN. Thus, for example, in simple ratio comparisons of MN/AF, we need to remember that we are not comparing like with like, and the derived relationship can be wildly out. Predictable ratios exist only in the simplest hypothetical populations (Savage, 1989).

A technical innovation, Cytochalasin-B. The conflict between "generation" and "dilution" was recognised fairly quickly and several protocols were suggested to counteract it. One obvious solution is to identify and confine scoring to those cells that have divided once, and once only, since the clastogen was given. This eliminates dilution by the overgrowth of undamaged cells coming round for the second time. The most popular and widely used method to achieve this, utilises a drug called Cytochalasin-B (Cyt-B) (Fenech and Morley, 1985; Fenech and Morley, 1986; Wakata and Sasaki, 1987). In the presence of this compound at appropriate dilution (2-6 mg/ml) the nucleus goes through mitosis, but the daughter cells fail to separate, leading to a bi-nucleate cell. Obviously, such cells must have divided once since Cyt-B was added, and MN scoring can be confined to this sub-set. Provided everything, apart from cell separation, is normal, the frequency of (MN/binucleate-cell) will be twice that which would have been found in once-divided mononucleate-cells. The frequency of binucleate-cells with MN will also be approximately twice that of once-divided mononucleate-cells. The use of Cyt-B is, of course, only a partial solution, since we only collect the MN formed from one mitosis. Therefore, any treatment effects, or modifications in PI will be reflected in the observed MN frequency. However, it is a very useful method now almost universally used for micronucleus studies, and it has helped to clear up a lot of the problems which plagued the early work. Cyt-B can be used in sequential "pulse" treatments to collect cohorts of cells at different times after treatment. This enables one to follow the generation and the dilution at different times after treatment. There is still a lot to learn about the action of Cyt-B. Curiously, only a proportion of cells seems to be trapped, irrespective of concentration; mononucleate cells with MN are always contemporary with binucleate ones. Some of the trapped cells will divide again if treatment is prolonged, but spindles become multipolar and there is much non-disjunction so such cells are useless for longer-term MN studies.

Chronic irradiation and chemical treatments. So far, we have viewed the problems of quantitative work on the relations of AF and MN assuming an acute dose of clastogen. If, however, a chronic dose is given - either by prolonged exposure time, or by incorporating a radioactive source into the nucleus, then we introduce an additional set of problems. This is a particular difficulty when chemical clastogens are used, as the



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majority of these are long-lived, and/or the molecules and lesions persist within the cells producing additional primary aberrations in subsequent cell generations. In practice, it is almost impossible to give anything approaching a clean acute treatment, as one can when using external radiation. There is much intra-nuclear change going on as the cell transits the various phases of the mitotic cycle, so it is not surprising that sensitivity to clastogen effects (aberration type and frequency, mitotic delay and perturbation, and probably effectiveness of repair) varies from one stage to another. With chronic treatment, each cell must "run the gauntlet" of these changes whilst damage production and repair are taking place, and the various effects will accumulate and confound. The repair processes will be continually busy, stretched and probably over-stretched, whilst the cell is trying to cope with the continuous influx of problems (rather like mending a leaking pipe whilst someone is boring holes elsewhere!). The overall effect is to introduce additional perturbations, frequent (often selective) cell death, and the conflict between "generation" and "dilution" will be considerably modified. Quite likely, the yield-time curve will have extra peaks and troughs and will not reflect the true sensitivity situation within the population. We always have to remember that the observed frequency of any event, with which we construct our graphs, and from which we draw our inferences, depends entirely upon the mixture of cells which is present in the sample scored (Savage and Papworth, 1991). Changes in this cell mixture can produce effects as profound as real treatment-induced changes. It often requires much wisdom to tell the difference.

References Carrano AV, Heddle JA. The fate of chromosome aberrations. J Theor Biol. 1973 Feb;38(2):289-304

Heddle JA. A rapid in vivo test for chromosomal damage. Mutat Res. 1973 May;18(2):187-90

Heddle JA, Harris JW. Letter: Rapid screening of radioprotective drugs in vivo. Radiat Res. 1975 Feb;61(2):350-3

Countryman PI, Heddle JA. The production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes. Mutat Res. 1976 Dec;41(2-3):321-32

Savage JR. Classification and relationships of induced chromosomal structual changes. J Med Genet. 1976 Apr;13(2):103-22

Buckton KE. Chromosome aberrations in patients treated with X-irradiation for ankylosing spondylitis. In: Radiation-induced Chromosome Damage in Man. Ishihara T and Sasaki M (eds) Alan Liss, New York. 1983:491-511.

Brock WA, Williams M. Kinetics of micronucleus expression in synchronized irradiated Chinese hamster ovary cells. Cell Tissue Kinet. 1985 May;18(3):247-54

Fenech M, Morley AA. Measurement of micronuclei in lymphocytes. Mutat Res. 1985 Feb-Apr;147(1-2):29-36

Braselmann H, Bauchinger M, Schmid E. Cell survival and radiation induced chromosome aberrations. I. Derivation of formulae for the determination of transmission and survival parameters of aberrations. Radiat Environ Biophys. 1986;25(4):243-51

Fenech M, Morley AA. Cytokinesis-block micronucleus method in human lymphocytes: effect of in vivo ageing and low dose X-irradiation. Mutat Res. 1986 Jul;161(2):193-8

Roberts CJ, Morgan GR, Holt PD. A critical comparison of the micronucleus yield from high and low LET irradiation of plateau-phase cell populations. Mutat Res. 1986 May;160(3):237-42

Das BC, Sharma T. The fate of X-ray-induced chromosome aberrations in blood lymphocyte culture. Mutat Res. 1987 Jan;176(1):93-104

Wakata A, Sasaki MS. Measurement of micronuclei by cytokinesis-block method in cultured Chinese hamster cells: comparison with types and rates of chromosome aberrations. Mutat Res. 1987 Jan;190(1):51-7

Degrassi F, Tanzarella C. Immunofluorescent staining of kinetochores in micronuclei: a new assay for the detection of aneuploidy. Mutat Res. 1988 Oct;203(5):339-45

Savage JR. A comment on the quantitative relationship between micronuclei and chromosomal aberrations. Mutat Res. 1988 Jan;207(1):33-6

Fenech M, Morley AA. Kinetochore detection in micronuclei: an alternative method for measuring chromosome loss. Mutagenesis. 1989 Mar;4(2):98-104

Savage JR. Acentric chromosomal fragments and micronuclei: the time-displacement factor. Mutat Res. 1989 Apr;225(4):171-3

Heddle JA. Micronuclei in vivo. In: Mutation and the environment, B. Mendelsohn ML and Albertini RJ (eds), Wiley-Liss, New York. 1990:185-94.

Tucker JD, Eastmond DA. Use of an antikinetochore antibody to discriminate between micronuclei induced by aneuploidogens and clastogens. In: Mutation and the environment, B. Mendelsohn ML and Albertini RJ (eds), Wiley-Liss, New York. 1990 :275-84.

Savage JRK, Papworth DG. Excogitations about the quantification of structural chromosomal aberrations. in: Advances in mutagenesis research, 3. Obe G (ed), Springer-Verlag, Berlin. 1991:162-89.

Müller WU, Streffer C. Micronucleus assays. In: Advances in Mutagenesis Research. Obe G (ed), Springer-Verlag, Berlin. 1994:1-134.

Streffer C, Müller WU, Kryscio A, Böcker W. Micronuclei-biological indicator for retrospective dosimetry after exposure to ionizing radiation. Mutat Res. 1998 Aug 3;404(1-2):101-5


Savage JRK. Micronuclei : Pitfalls and Problems. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):229-233.



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Cancer Prone Diseases Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Educ/Cancers_e.html DOI: 10.4267/2042/37684


I. CHROMOSOME INSTABILITY SYNDROMES

II. RETINOBLASTOMA / LI-FRAUMENI SYNDROME

III. HAMARTO-NEOPLASTIC SYNDROMES

I. CHROMOSOME INSTABILITY SYNDROMES A handfull of rare genetic diseases associate chromosome instability, DNA replication and/or repair anomalies, some shared clinical features, and an increased risk of cancer. These diseases are characterized by a high level of spontaneous chromatid breaks and chromosome rearrangements, and/or a hypersensitivity to clastogens (see an introduction to chromosomal aberrations). The genes implicated in these diseases are partly known and seem to have a role in DNA repair and/or in the cell cycle regulation. If lesions into DNA are not correctly repared, mutations and rearrangements will accumulate, until, by chance, one of these mutations results in the activation of an oncogene or in the inactivation of the allele(s) of a tumor suppressor gene. Whence, chromosome instability syndromes are paradigmatic.

Fanconi Anemia (FA) Autosomal recessive; q2 = 1/40 000.

Clinics: - Growth retardation. - Skin abnormalities: hyperpigmentation and/or café

au lait spots.

- Squeletal malformations, particularly radius axis defects.

- Progressive bone marrow failure → bone marrow aplasia.

Neoplastic risk: - Myelodysplasia and acute non lymphocytic

leukemia: in 10% of cases; i.e. a 15000 fold increased risk; other cancers (5%).

Cytogenetics: - Spontaneous chromatid/chromosome breaks. - Hypersensitivity to the clastogenic effect of DNA

cross-linking agents. - Slowing of the cell cycle (G2/M transition). Genes: - 4 complementation groups; genes FACC, FA1

Ataxia Telangiectasia (AT) Autosomal recessive; q2 = 1/40 000.

Clinics: - Telangiectasia: facial region exposed to sunlight. - Progressive cerebellar ataxia. - Combined immunodeficiency → infections → 80%

of deaths. Neoplastic risk: - T-cell malignancies (a 70 fold and 250 fold increased

risks of leukaemia and lymphoma respectively) → 20% of deaths.

Cytogenetics: - More than 10% ofs mitoses bear a chromosome

rearrangement in 7p14, 7q35, 14q11, or 14q32 (illegitimate recombinations between immunoglobulin superfamilly genes Ig and TCR).

- Clonal rearrangements further occur → T-cell malignancy.

- Lenthening of the cell cycle (slower S phase).

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Radiosensitivity: - High sensitivity to radiations and to radiomimetic

drugs. Genes: - Gene in 11q23: ATM probable role in DNA repair,

recombinaison, and in the cell cycle control.

Note: Heterozygous for AT may be at increased risk of breast cancer.

Bloom Syndrome (BS) Autosomal recessive; q2 = 2/100 000.

Clinics: - Sun sensitive telangiectatic erythema. - Dwarfismn. - Normal intelligence. - Combined immunodeficiency → infections. Neoplastic risk - Carcinomas (30%), lymphomas (25%), acute

lymphocytic and non lymphocytic leukemias (15 % each), ...

- Mean age at first cancer onset: 21 yrs; more than one cancer in a given patient.

Cytogenetics: - Spontaneous chromatid breaks. - Diagnosis on the highly elevated spontaneous sister

chromatid exchange rate (90 per cell). - Slowing of the cell cycle (lenthening of the G1 and S

phases). Gene: - Gene BLM , codes for a DNA helicase.

Xeroderma pigmentosum (XP) Autosomal recessive; q2 = 0,4/100 000.

Clinics: - Sun sensitiviromic lesions → skin cancers. - Photophobia. - Neurologic features. Neoplastic risk: - Multiple cutaneous and ocular tumors as early as

from the age of 8 yrs (in sun exposed zones). Cytogenetics: - Normal level of breaks and chromatid exchanges. - Hypermutability of the cells under UV irradiation. Genes: - 9 complementation groups. Genes ERCC (excision

repair cross complement) and XP (ex: XPAC): mumerous and dispersed on various chromosomes; role in DNA repair (helicases) and in the complex repair/transcription factor.

II RETINOBLASTOMA and LI-FRAUMENI SYNDROME These two diseases are examples of the involvement of tumor suppressor genes; they are also of interest for various reasons; retinoblastoma mixes constitutional and acquired chromosome features, the gene Rb is autosomal recessive but the disease appears to be

autosomal dominantly inherited, due to rare events multiplied by numerous cells and conditional probabilities; Li-Fraumeni syndrome is a rare disease discovered from epidemiological studies, and P53 is, otherwise, THE gene involved in 50% of the cancers. Both genes are involved in the cell cycle regulation and arrest. If the cell cycle is not stopped until the background lesions into DNA are correctly repared, mutations and rearrangements will accumulate along the cycles, until, by chance, one of these mutations results in the activation of an oncogene or in the inactivation of the allele(s) of a tumor suppressor gene.

Retinoblastoma Cancer prone disease at increased risk of the cancer of the retina called (also) retinoblastoma - Embryonnic tumor of the neurectoderma. - Appears most often in childhood. - There are sporadic forms (with a negative familly

history) and hereditary forms. - There are unilateral forms (mostly in the sporadic

cases) and bilateral forms (mainly in the hereditary cases).

- Hereditary forms seem to be transmitted as an autosomal dominant disease with a 90 % penetrance.

- Patients having a retinoblastoma have an increased frequency of other cancers, in particular of osteosarcoma and pinealoma.

- In a (very) few cases, a visible chromosome 13 deletion may be seen on the constitutionnal karyotype, and, according to the lenght of the deletion, the patients present with dysmorphic features and mental impairment (as usual for unbalanced constitutional anomalies), in addition to the cancer(s) of the retina they have.

These features are unusual, and some appear contradictory... They will be explained by the two-step inactivation mechanism, according to AG Knudson (1971): both alleles of a tumor suppressor gene must be inactivated to let the cancer develop. - 1st event : deletion

• In a germ cell: hereditary form (therefore each of the cells of the patient, in particular each of the cells of each of the 2 eyes bear the deletion: that will considerably increase the risk of multiple retinoblastomas in 1 eye, or of bilateral retinoblastoma: conditional probability P(1st allele) X P(2nd allele) with the first proba already = 1).

• or in a retinoblast: sporadic form. - 2nd event: 2nd deletion: in a retinoblast (somatic

deletion). - Finally: when homozygosity for inactivation is

reached → the tumor develops. The gene is recessive; it however seems to be transmitted as an autosomal dominant disease in hereditary forms: the hereditary mutation, first event,

Cancer Prone Diseases Huret JL


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has a probability 1/2 to be transmitted to the "patient". If, by some means or other, the (second) somatic hit has a probability close to 1, then, the resulting probability to have a retinoblastoma will be 1/2 x 1 = 1/2, what is characteristic of autosomal dominant transmission. The somatic event's probability is close to 1 (the "some means or other" above noted is the result of the low rate of mutations multiplied by the great number of cells at risk). This somatic hit is produced either by: - Loss of the normal chromosome 13 → monosomy

with only the deleted 13 (hemizygosity). - Loss of the normal chromosome 13 and duplication

of the deleted 13 (homozygosity). - Deletion within the normal 13 where `the important

gene' sits. - Mutation (or any other kind of inactivation) of `the

important gene' present on the normal 13.

This gene has been called Rb, and belongs to the class of tumor suppressor genes (earlier "antioncogenes"), as, when they are normal and active, they prevent from cancer.

Rb: gene sitting in 13q14; 180 kb, 27 exons, mRNA of 4,7 kb --;> P105 Rb protein: can form complexes with nuclear oncogenes; phosphorylated in S and G2/M phases of the cell cycle; unphosphorylated in G0 and G1 and associated with E2F; anti proliferative activity.

LI-Fraumeni syndrome and P53 1/3 of the population will have a cancer; Besides, exist familial cancers; more than a hundred genetic diseases are accompanied with an increased risk of cancers (either specific or pleiotropic). In the general population, if a given person has a cancer: → risk is increased by 2 or 3 in the family. In certain types of familial cancers: → risk X 103 ! How to suspect an hereditary cancer: - Too early in life; - More than 1 cancer in 1 patient; - Positive family history (other cancers, more than

usual, in the family). In 1969 FP Li and JF Fraumeni define a syndrome : - Autosomal dominant,

- With: breast cancers, sarcomas, brain tumors, leukemias, ...

- Inclusion criteria: 1 individual having a sarcoma and at least 2 related persons with a sarcoma or a carcinoma.

P53: - Gene sitting in 17p13; 20 kb, 11 exons (1st exon is

non coding), mRNA of 3,0 kb. - The protein presents a transactivation domain, a

DNA-binding domain, nuclear localization signals and a tetramerization domain.

- Transcriptional regulator: in response to DNA damage, P53 activates the transcription of genes implicated in the cell-cycle arrest and genes implicated in apoptosis; these activations allow either the cells to repair DNA damage before entering further in the cell cycle, or to be eliminated.

- P53 is the most frequently (50%) mutated gene in cancers (with loss of fonction of the second allele) (SOMATIC MUTATION = ACQUIRED ANOMALY).

- P53 is found mutated as an inborn condition in most (but not all!) patients with the congenital genetic disease named Li-Fraumeni syndrome (GERMINAL MUTATION = CONSTITUTIONNAL ANOMALY).

III HAMARTO-NEOPLASTIC SYNDROMES Hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; these diseases are heritable; hamartomas are benign proliferations that have a potential towards neoplasia; patients may also be at increased risk of benign and malignant tumors of other tissues and organs. The genes known so far are tumor suppressor genes, but no common fonction has yet been established. This article should be referenced as such:

Huret JL. Cancer Prone Diseases. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):234-236.



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Embryology, Semiology, Dysmorphology Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyEmbryoEng.html DOI: 10.4267/2042/37685

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology HANDS The palm is characterized by: - flexion creases: generated by mouvements of

the skin in relation to joints motility. - dermatoglyphics: dermal ridges on fingers, on

the palm, and on the planta.

CREASES: - fingers: 2 flexion creases for each finger

(except the thumb: only 1 crease). - finger-palm creases. - palm : 3 normal creases:

• longitudinal radial crease (LRC in the Figure).

• proximal transverse crease (PTC). • distal transverse crease (DTC).

Fusion of (complete fusion or bridge between) the 2 transverse creases is called single transverse crease, transverse palmar crease, or simian crease.

DERMATOGLYPHICS: Triradius: point of convergence of ridges from 3 different directions. Normally, there is: - 1 axial triradius: normally in t, close to the

wrist. - 4 subdigital triradii (a.b.c.d.). - On the pad of the distal phalanx, sometimes

on thenar or hypothenar eminences, are triradii, accompanied with the following patterns: • worl: 2 triradii. • loops and equivalents (ulnar or radial

orientated): 1 triradius. • arches: 0 triradius.

From each palmar triradius a, b, c, d, and t, is drawn the 3 lines separating the ridges at this convergence point. The longest is the main line (-- A B C D & T), ending

at a side of the palm numbered from 1 to 14 (see Figure).

- T normally ends in 13. - transversality index = A+B+C+D = 27 on

the Figure.

On the fingers may be counted the number of ridges from the center of the pattern to the triradius. (example here: n = 4); in case of an arch, n=0. For the 10 fingers, males have 140 - 145 ridges, and female have 120 - 130 ridges, according to the formula: n = 187 - (30 * no of X) - (12 * no of Y); this may be very useful in the Underground to determine the sex of the person next to you, and to pass the time.

METACARPO- OR METATARSO-PHALANGEAL ANOMALIES NUMERICAL ANOMALIES:

- Polydactyly: existence of supernumerary fingers. example: palmar and/or plantar hexadactyly trisomy 13.

- Syndactyly: union of 2 or more fingers or toes (more or less complete, only involving the skin or with bone fusion).

SIZE ANOMALIES: - Brachydactyly: short fingers. Various types

according to which phalanx is involved (e.g. brachymesophalangy: short medial phalanx).

- Brachymetacarpy: short metacarp(s) (example: in Turner syndrome).

SHAPE ANOMALIES: - Clinodactyly: bend of fingers (often the 5th, as

in trisomy 21). - Camptodactyly: irreductible flexion of the 2nd

phalanx on the 1st (without bone involvment). - Arachnodactyly: long and slender fingers.

Embryology, Semiology, Dysmorphology Huret JL


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As isolated signs, these anomalies are often transmitted as autosomal dominant traits.



239

FACE: Semiology and Embryology



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241

HEART: Embryology and Malformations



242



243

GENITALIA: Embryology


Huret JL. Embryology, Semiology, Dysmorphology. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):237-243.



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Trisomy 21 Jean-Loup Huret, Pierre-Marie Sinet

CNRS UMR 8602, Faculté de Médecine Necker Enfants Malades, Paris, Franc (JLH, PMS)


Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyTri21Eng.html DOI: 10.4267/2042/37687


The most frequent viable chromosome disease.

Like other inborn autosomal chromosome diseases, associates dysmorphia + psycho-motor delay, and possible visceral malformations (found in more than 1/3 of cases); a medico-pedagogic care and follow up must be undertaken.

I. EPIDEMIOLOGY (A question on epidemiology would also include recurrence risks according to the karyotypic findings: see paragraph on the karyotype).

1,5 /1 000 births. Sex ratio: 3 males/2 females. Increased median maternal age (34 years).

Maximal trisomy 21 births from mothers aged: • 28 yrs (but this is only because the maximal

birth rate is for this maternal age). • Around 37 yrs. • The risk increases with maternal age: <0.1%

below 30 yrs; between 0.1% and 1% at ages 30-40 (0.2% at 34 yrs, 0.5% at 38 yrs, 0.7% at 39 yrs); >1% above 40 yrs (5% at 46 yrs, 15% at 50 yrs).

Trisomy 21 Huret JL, Sinet PM


245

II. CLINICAL EXAMINATION 1 - Dysmorphic syndrome associating (to various extend):

• Evocative face +++: o Frequent microcephaly, short neck, flat

occiput and brachycephaly; o Moon-shaped face; o Flat nasal bridge; o "Socket" nostrils; o Hypertelorism (or pseudo-hypertelorism); o Epicanthus (regresse with age); o Upward slanting palpebral fissures; o Brushfield spots in the iris

(pathognomonic, detectable in blue eyes). o Macroglossia; glossitis exfoliativa

(geographic tongue); scrotal tongue at late childhood and in adulthood;

o Mouth frequently open; frequently open mouth;

o Narrow/ high arched palate; high arched narrow palate;

o Late appearing/malformed teeth (numerical anomalies, agenesis of lateral incisors...);

• Hands and feet: o Short and broad; o Brachymesophalangia of the 2nd and 5th

fingers; o Clinodactyly of the 5th finger; o Flat feet; o First toe set apart from the others by a

gap, with a crease. • Dry skin, mottled skin (livedo), with frequent

infections around orifices. • Hyperlaxity of ligaments. • Frequent umbilical hernia.



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2 - Psycho-motor delay (constant): • Hypotonia +++ at birth (hold his head at 6

mths, sits at age 1 yr, walks at age 2 yrs). • The mental retardation, not obvious in the

infant, will soon become manifest. • Children's behaviour: o Affectionate, gentle, cheerful; o Language difficulties; o Like to play, to mime, to tidy up

meticulously; o Normal memory.

• Seizures (in 3% to 9%, as compared to 1% in the general population).

3 - Dermatoglyphics: • Transverse palmar crease in 75% of cases.

Beware: it is also present in 1% of the general population; therefore, out of 8 transverse palmar creases at birth, 7 come from the general population and only 1 from a Down syndrome baby (1% risk X 699/700 births versus 75% risk X 1/700 births): one MUST NOT make a diagnosis of trisomy 21 on this isolated sign and throw parents into a panic.

• Axial triradius in t" (in 75%). • Transversality index > 30.

This association of signs implicates that visceral malformations have to be searched for, as they can burden the vital prognosis and impose that emergency treatments be started.

4 - Malformations (45% of cases): • Heart (40%): o Atrioventricular septal defect (10 %); o Ventricular septal defect (10 %); o Patent foramen ovale (5 %); o Persistence of ductus arteriosus (5

%)... • Digestive (10 %): o Duodenal stenosis (1/3 of duodenal

stenosis are found in trisomy 21patients); o Imperforate anus...

• Ocular: o Cataract (congenital or acquired); o Astigmatism; o Myopia; o Strabismus; o Congenital glaucoma; o Nystagmus.

5 - Other: • Hematologic: o ‘Transient leukemoid reaction’ may occur o Sometimes with a relapse as acute leukemia

(lymphoblastic (ALL) or more frequently non-lymphoblastic (ANLL) leukemias; M7-ANLL (megakaryocytic) is particularly frequent. Watch the hypersensitivity to methotrexate.

• Immunological: o Tuberculine hyporeactivity; o Immune deficiency.

• Metabolic: o Hyperuricemia; o Abnormal glycemia; o Increased TSH (frequent); hypo or hyper

thyroidy.

III. DIAGNOSIS: THE KARYOTYPE Proves the diagnosis, allows/implicates a genetic counseling: Recurrence risk is about 1 % if the anomaly is de novo, more if one of the parents is a translocation carrier.

Free and homogeneous trisomy 21 (92,5 % of cases): • Sporadic (de novo) cases. • Role of maternal age (see above in

epidemiology). • Recurrence risk: 1 to 2 %. • Karyotype: 47,XY,+21 ou 47,XX,+21. • Due to meiotic non-disjunction: o Of maternal origin:

- lst division: 70 % - 2nd division: 20 %

o Of paternal origin: - lst division: 5 % - 2nd division: 5 %

Free trisomy 21 in mosaic (2,5 % of cases): • Sporadic cases. • Karyotype: 46, XY / 47, XY,+21 or 46, XX /

47, XX,+21. • Post zygotic event (mitotic). • Most often, the phenotype is typical, at times

attenuated.

Trisomy 21 due to translocation : • De novo or transmitted from a parental

translocation (being a balanced translocation in the parent); genetic coonseling is especially needed in the latter case.

• Karyotype with 46 chromosomes; the extra chromosome 21 is most often translocated with another acrocentric (groupe D: 14, 13 or 15 or groupe G: 21 or 22) chromosome; example: 46, XY, t(14;21).

• Genetic counseling and recurrence risk: o t(Dq;21q) et t(21q;22q)

of maternal origin: risk = 15 % of paternal origin: risk = 5%

o t(21q;21q): risk = 100 %: either → trisomy 21 or → spontaneous miscarriage (monosomy 21).

o Other: � Partial trisomy 21 (rare). →

(the segment responsible for most of the syndrome/phenotype is band 21q22.3.



247

� Associated with other chromosome anomalies (rare).

IV. EVOLUTION • Statural delay (adult = 1,50 m); weight excess

(→ diet). • Voice becomes hoarse. • Pelade may appear. • Puberty is delayed but normal; poor libido; • Fecondity in the female (→ contraception). • Hypothyroidy, Basedow (→ T3, T4, TSH,

reverse T3 regular determination). • Mental development: o Intelligence quotient (IQ) = 50 (mean

(and median)); between 30 and 80; Gaussian curve, as in the general population but with a mean shift to 50 instead of 100; vary according to age);

o Social insertion: partly according to the familial environment, the guidance and reassurance that the family receives, and according to the medical, paramedical, and pedagogic cares instaured;

o Psychomotor therapy from the age of 6 mths, kinesitherapy, orthophony latter; nursery school, followed if possible by a class of handicapped children within a normal primary school; latter, school and professional school in specialized institutions; apprenticeship, manual professionnal activity; insertion into active life; they must not stay at parents home, where they would remain with a child status, and finally where they would grow old faster as parents get old.

• Early aging: o Behaviour may suddenly switch from

that of a happy and sociable child to a sad, inactive and inexpressive adult;

o Risk of senile dementia (Alzheimer disease).

V. PROGNOSIS • Life expectancy, formerly poor, has greatly

increased, due to antibiotherapy and surgery. • Prognosis can be impaired by:

1 - The extreme susceptibility to infections. 2 - Malformations, cardiac malformations in particular. 3 - Acute leukemia (in 1 % of trisomy 21 infants/children, i.e. 20 times more frequently than in the general population).

• Intellectual prognosis: (see evolution).

VI. TREATMENTS • Surgery in the case of malformation(s). • Antibiotherapy of infections; antifungal

treatment of athletic foot. • Medical-paramedical-pedagogic cares;

psychomotor therapy, kinesitherapy, orthophony. • Thyroid function repeated examinations (once

a year). • Ophtalmologic tests (watch the

hypersensitivity to atropine), auditive tests. • Cervical X-rays (cervical instability→ risk of

cervical vertebrae dislocation). • Flat foot (special shoes, tricycle are

recommended). • Flat dorsum (swimming recommended). • Keloid scars (surgery only when needed,

avoid plastic surgery). • Artistic creativity should be developed and

supported. This article should be referenced as such:

Huret JL, Sinet PM. Trisomy 21. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4): 244-247.



248



Other Constitutional Chromosome Diseases Jean-Loup Huret, Claude Léonard



Online updated version : http://AtlasGeneticsOncology.org/Educ/PolyConstitAutreEngl.html DOI: 10.4267/2042/37686


GENERAL COMMENTS Imbalances concerning gonosomes are less deleterious than those affecting autosomes; Imbalances leading to an excess of gene dosage (i.e. duplications, trisomies) are less deleterious than those resulting in a deficit (i.e. deletions, monosomies). Bias of sampling: the most deleterious chromosome imbalances are not seen but result in early miscarriages; miscarriages and stillbirths occur in other syndromes, and only the less deleterious are compatible with life. Some signs are characteristic of the disease. They are due to a gene effect or to the combination of genes effects. their association can be called a contiguous gene syndrome (see below). Other signs are aspecific of the region involved; they are the result of general gene imbalance and/or cell division disturbances, and may be found in many chromosome syndromes: growth retardation, microcephaly, mental retardation, low set ears... can be found in various disease with no gene similarity. Type/contertype: trisomy 4p syndrome (not herein described) exhibit some signs which are the opposite of del(4p) syndrome (e.g. flat/high forehead, aplasic/large glabella, prognatism/microretrognatism). In trisomy 4p, genes located in 4p are in 3 sets, while in del(4p) these genes are in only 1 set. This is an example of probable gene dosage specific effects. Haploinsufficiency: is a term used in case of a deleted segment with deleterious effects; it means that the remaining haploid set of gene(s) is insufficient to allow a normal function. Critical region: it was previously thought that a trisomy phenotype was due to the global excess of the extra chromosome (e.g. trisomy 21), and a deletion syndrome to the haploinsufficiency of the whole deleted segment. With the description of cases with overlapping imbalances, it became clear that some

regions of imbalance had more deleterious effects, while others induced only mild disturbances. The critical segment is, in some instances, very narrow: band q22.3 is responsible of most of the trisomy 21 phenotype; it may even be smaller: the 200 kb critical segment in del(4p) syndrome. In the latter case, one has even evoked the notion of "contiguous gene syndrome". Continuous genes syndrome: some Mendelian inherited diseases have been known for long, and their deleterious effect well described. It has happen that a given patient had presented with the addition of phenotypes from different inherited diseases. A well known example is that of a patient with the addition of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and Mc Leod syndrome. This patient had a deletion in Xp21, where all these genes map. Cryptic rearrangements/imbalances: it is likely that a percentage of chromosome imbalances remain undetected and/or undetectable: some of these imbalances are probably cause of major anomalies; the location of the chromosome imbalance may not be suspected if the phenotype is not reminiscent of a well known syndrome; others cryptic imbalances may have no, or slight effects, and will never be uncovered (another bias of sampling!).

OTHER AUTOSOMES DISEASES A - DELETION 4p (Wolf-Hirschhorn syndrome / Pitt-Rogers-Dank syndrome) • Karyotype: deletion of band 4p16 gives full

phenotype; critical segment narrowed to 200 kb. • Clinics: o hypotrophy, low birth weight: 2 kg.

Other Constitutional Chromosome Diseases Huret JL, Leonard C


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o microcephaly, high forehead, large glabella, broad nose in prolongation of the eyebrows line: greek helmet aspect.

o hypertelorism, ocular malformations, hare-lip / cleft palate.

o long, slender, manicured fingers. • Malformations: o heart (50%). o ocular; in particular colobomata (25%).

• IQ = 20; seizures; often bedridden.

B - DELETION 5p (cri-du-chat syndrome) • Karyotype: deletion of 5p14-p15 most often;

critical segment narrowed to 5p15.2 (about 2 Mbases); the deletion is de novo in 85% of the patients, and 15% are familial cases of parental balanced rearrangement

• Epidemiology: 0.02/1 000 births. • Clinics: o Typical high-pitched cry in the

newborn (like a kitten) Microcephaly, round moon-shaped face, hypertelorism, broad nasal bridge, downward slanting o palpebral fissures, and micrognathia;

growth retardation o Triradius axial in t'. o Hypotonia in the newborn; hyperactivity,

tantrums, destructive behaviour is frequent in the adult; autistic-like features may be present; heavy psychomotor retardation (IQ may be at 20).

• Malformations: rare.

C - TRISOMY 8 MOSAICISM • Epidemiology: sex ratio 3M/1F; increased

parental mean age. • Clinics: o High forehead, everted lower lip. o Discrete dysmorphia. o Dermatoglyphics: deep

palmar/plantar furrows. • Malformations: kyphoscoliosis, hemivertebrae

and other osteoarticular disorders. • I Q: 50 to 70 mainly; however, cases with

normal intelligence and no visible malformation remain undetected.

D - TRISOMY 9p • Karyotype: critical segment likely to be in

9p22-p24. • Clinics: microcephaly, deeply set eyes, broad

nose. • Malformations: rare. • I Q = 50.

E - TRISOMY 13 (Patau syndrome) • I. Epidemiology: o 0.1 / 1 000 births.

o Increased parental age. o Normal pregnancy duration. o Life expectancy: frequently found in

early miscarriages, and in late miscarriages; stillbirths are common, and babies often die in the neonatal period; very few reach adulthood.

• II. Clinics: o Microcephaly, receding forehead. o Microphtalmia/anophtalmia,

colobomata of the iris, cataract. o Arrhinencephaly, probocis. o Hypotelorism. o Scalp defect (in relation with neural

tube fusion defects). o Hare-lip / cleft palate. o Umbilical hernia: 1/3 of cases. o Genitalia: cryptorchidy in the male,

uterus bicornis (constant) and vagina duplex (often) in the female.

o Fingers in flexion position; postaxial polydactyly 80 % (hands and feet); club foot; dermatoglyphics: axial triradius in t"; thenar pattern.

• III. Malformations: constant, heavy, leading to early death in most of the cases.

o Central nervous system: � Arhinencephaly (50 %). � Hypoplasia of the corpus

callosum (20 %). � Hypoplasia of the frontal

lobe. � Spina bifida.

o Ocular: � Micro/anophtalmia (90 %). � Coloboma. � Retinal dysplasia. � Luxation or absence of lens.

o Cardiac (constant): � Ventricular septal defect. � Patent foramen ovale. � Persistence of ductus

arteriosus � Tetralogy of Fallot.

o Renal (50 %): � Hydronephrosis. � Polykystic kidneys ...

o Digestive (50 %): � Malrotation of the intestine. � Malformation of the

pancreas. � Gallbladder agenesis.

o Bones: � Spina bifida. � Rib malformations. • IV. Karyotype:

o Most often free and homogenous trisomy.



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o Sometimes translocation t(13q 14q). o Sometimes mosaic trisomy.

F - DELETION 18p (Edwards syndrome) • Brachycephaly, ptosis, broad nose, irregular

teeth. • Kyphoscoliosis. • Holoprosencephaly (10%). IQ = 50; may have psychiatric behaviour.

G - DELETION 18q • Karyotype: deletion of 18q21-qter most often;

critical segment maps to 18q23. • Clinics: o Severe hypotonia (frog-like). o Midface hypoplasia; carp-shaped

mouth. o Tapered fingers. o Hearing impairment o Growth retardation

• Malformations: o Ocular: constant. o Osteoarticular. o Genitalia. o Variable IQ, from 30 to over 70.

H - TRISOMY 18 • I. Epidemiology: o 0.2 / 1 000 births. o Increased parental age. o Pregnancy duration is often prolonged. o Life expectancy: frequently found in

miscarriages; stillbirths are common, and babies often die in the neonatal period; very few reach adulthood.

• II. Clinics: o Hydramnios; single umbilical artery

frequently. o Low birth weight: 2,3 kg. o Constant sign: hypoplasia of the first

branchial arch, which implicates: → Low set ears → Microretrognatism

o Pierre Robin syndrome: � Microretrognathism, � Cleft palate, � Glossoptosis.

o Microcephaly (40 %), dolichocephaly. o Short neck with excess of skin . o Faun-like ear. o Short thorax and sternum, making the

abdomen looking long. o Hernias: diaphragmatic, umbilical,

inguinal. o Cryptorchidism (30 %). o Clubfoot; irreducible flexion of

forearms; dysplastic nails, absence of distal

flexion crease of fingers; clenched fingers with overlap of the 2nd and 5th onto the 3rd and 4th; dermatoglyphics: frequency of arches.

• III. Malformations: constant, heavy, leading to early death in most of the cases.

o Cardiac: constant. � Ventricular septal defect. � Patent foramen ovale. � Persistence of ductus

arteriosus � Valves anomaly, in

particular mitral valve o Renal (1/3): mostly horseshoe kidney,

hydronephrosis, polykystic kidneys, hyploplastic kidneys.

o Digestive: frequent; Meckel, anal atresia; pancreas anomalies.

o Brain o Bones: spina bifida, hemivertebrae,

absence of clavicle. • IV. Karyotype o Most often free and homogenous

trisomy. o Frequency of doubles aneuploidies and

mosaics.

DYSGONOSOMIES AND RELATED SYNDROMES

A - TURNER SYNDROME In a few words, Turner syndrome (or Ullrich-Turner syndrome) is a syndrome of growth retardation and impuberism with frequent cardiovascular or renal malformation, normal intelligence, due to a chromosome imbalance: 45, X and variants. • I. Epidemiology: o 0.4/1000 female births (but 20 % of

chromosome anomalies found in early miscarriages, i.e. about 10% early miscarriages).

o Due to the loss of the maternal gonosome (a X) in 20-30% of cases, or of the paternal gonosome (a X or a Y) in the remaining 70-80%.

• II. Clinical ascertainment/examination: The diagnosis can be evoked either:

o In the newborn (from dysmorphia and/or malformations), or:

o In the girl (from growth retardation, impuberism).

1 - Neo-natal form: o Prenatal (and postnatal) growth

retardation o Single umbilical artery frequently. o Bonnevie-Ullrich (BU) status

associating:



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� Lymphoedema of hands and feet (tough, non inflammatory, regressive at age 2 yrs).

� Excess of skin and webbed skin on the nucha (pterygium colli). 1/3 of BU are found in Turner syndrome, and 75 % of Turner have a BU In the presence of this symptomatology, a karyotype will be undertaken and (cardiac, renal) malformations will be searched for.

2 - In childhood or adolescence: o Small size (adult < 1,45 m). o Triangular shaped face, looks sad. o Hypertelorism. o Blepharoptosis. o Possible epicanthus. o Downward slanting palpebrale

fissures. o Short neck. o Pterygium colli in more than half

cases. o Low hair line. o High-arched palate. o Micrognatism. o Low set hears o Shield chest. o Widely spaced nipples. o Short 4th metacarpal. o Cubitus valgus (increased carrying

angle of the elbow). o Radius curvus (Madelung's

deformity). o Sinking of internal tibial plateau (sign

of Kosowizc in the adult). o Osteoporosis (and fracture increased

risk) above 45 yrs. o Multiple pigmented nevi; vitiligo

and/or café-au-lait spots. o Risk of keloid scars (surgery only

when needed, avoid plastic surgery). o Dermatoglyphics: number of digital

crests = 187 - (30 * X) - (12 * Y) (herein = 157). o Hypoplastic nails. o Infantile external genitalia. o Hypoplastic uterus. o Amenorrhea and sterility. o Absence of breast development. o Rare pubic pilosity. o Normal or subnormal intelligence;

the (slight) cognitive defects are limited to visual-spatial/perceptual abilities, attention, motor function, and nonverbal memory. May be partly due to psycho-social suffering, but also to genetic imbalances and their various consequences (e.g. hormone deficiency).

Malformations: o Cardiovascular (20-30%): aortic

coarctation (10-15 %) which may lead to death

by dissection or rupture of the aorta; bicuspid aortic valve; left superior vena cava, and other malformations; in the presence of aortic coarctation in a girl, a Turner syndrome must be evoked.

o Renal (40-50 %): horseshoe kidney, hydronephrosis...

o Congenitally dislocated hip, scoliosis o Sense-organs: deafness (impaired

hearing in up to 40%), myopia, cataract, strabismus.

o X linked recessive inherited traits have the same frequency in Turner syndrome and in the male, since they both have only 1 X; this frequency is that of the allele (e.g. daltonism, hemophilia, Duchenne de Boulogne myopathy...).

• III. Diagnosis: the karyotype: o 45, X homogeneous: 55 % of cases. o Isochromosomes: i(Xp), i(Xq);

deleted chromosomes: del (Xp), del (Xq); rings: r(x); mosaicisms... → phenotypes are more or less evocative of Turner syndrome some patients having been fertile.

o Most of the phenotypic traits are due to Xp deletion, and only ovarian failure is consistently associated with Xq deletions.

• IV. Assessments: o Ovarian failure (sex steroid

deficiency and amenorrhea). o Streak gonads (germinal cells regress

at the 3rd month in utero; biopsy is not needed). o Impaired glucose tolerance;

hypertension (20-30%). o Autoimmune thyroid disease (T4,

TSH, thyroid-antibody titer determinations). o X-rays (skeleton, urinary system,

heart). • V- Differential diagnosis: o Other disorders with Bonnevie-

Ullrich status. o Gonadic dysgenesia. o Other disorders with primary

amenorrhea; e. g.: XY females (sex reversal). • VI. Treatments: o Surgery of malformations. o Gonadectomy if a Y chromosome is

present in mosaic (neoplastic risk). o Growth hormone and oestrogens to

manage growth failure and to induce menarch and secondary sexual characters and menarche and to prevent osteoporosis.

o Psychological support (sterility).

Comments: Genes implicated in the syndrome are thought to be localised in the region of the gonososomes which escape X inactivation; the various clinical manifestations may either be due to



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haploinsufficiency of specific genes (in the pseudoautosomal region of X), aneuploidy effects (e.g. on meiosis), and/or fetal suffering from the lymphoedema.

B - KLINEFELTER SYNDROME

In a few words, Klinefelter syndrome is a syndrome of a normal or gynecoid male with normal intelligence or mild retardation, infertility, and possible behaviour or psychiatric problems, due to a chromosome imbalance: 47, XXY and variants. • I. Epidemiology: o 1.5 /1 000 male births. o Increased maternal age. o The extra X comes more often from

the mother. • II. Clinical ascertainment/examination: o Wide variability in clinical

expression: o Rarely diagnosed in childhood (from

mental retardation or non specific anomalies of genitalia),

o More often at puberty (from gynecomastia, small testes),

o Or when consulting for infertility. o Physical aspect is often normal, o They may present with tallness and

macroskelia, o Or with gynecoidy (gynecoid obesity:

25 %; gynecomastia: 15-25 %; bi-trochanteric diameter > bi-acromial diameter).

� Normal penis. � Small, indolent testes. � Normal or rare, feminine

shaped pubic pilosity. � Libido diminished;

impotence at age 30 yrs is frequent. � Sterility. � Normal or moderately

delayed intellectual development. � Dyslexia/dysphasia and

frontal-executive dysfunction. � Psychiatric behaviour is not

rare. o 50-fold increased risk of developing

breast cancer as compared to normal males (and 8 times less than in females, as the women’s risk is 400 times that of men) (nearly 10% of breast cancers in males are found in Klinelter patients).

• III. Diagnosis: the karyotype: o 47 XXY homogeneous: 80 % of

cases. o XXXY, XXXXY, XXYY: 10 %. o In mosaic: 5-10 % (may (rarely) be

fertile). • IV. Assessments:

o High gonadotropins and low testosterone plasma levels.

o Azoospermia in most non-mosaic cases; however, intratesticular residual foci of spermatogenesis may occasionally be found, and mature spermatozoa may permit paternity using intracytoplasmic sperm injection.

o Biopsy (not needed): seminiferous tubes atrophia, Leydig hyperplasia.

Treatment: testosterone replacement therapy to correct the androgen deficiency and to provide virilization; can also has positive effects on mood and self-esteem. C - FRAXA and FRAXE SYNDROMES (Fragile Xq or fra(X)(q28))

• I. Epidemiology: o FRAXA: 0.2 / 1 000 male births and

0.1 / 1 000 female births. o FRAXE: 0.02/ 1 000 male births.

• II. Clinics: o The face reminds of the one found in

trisomy 8. o Macrocephaly. o High forehead. o Midface hypoplasia. o Large nasal root. o Prognathism. o Thick lips. o High palate. o Large, unfolded ears. o Macroorchidy. o Fertility is often normal.

• III. Mental development and psychiatric behaviour (paragraph written by Denis Reserbat-Plantey):

o In the male: � Mental retardation is mild to severe (mean

IQ = 50): from a delay in school training to the impossibility to acquire writing and reading skills. The Fragile Xq young child is often hypotonic; in the more severe forms, a psychomotor delay is already present (delay in walking...).

� Speech difficulties: delay language appearance, dysarthria, omissions, mumblings, echolalias (tendency to repeat the same sentences and to ask the same questions).

� Behaviour problems: anguish, attention deficit, hyperactivity, impulsiveness, escape of glance, resistance to change, aggressiveness, self-mutilation, stereotypies (wings beating, "flapping") and oddities. Sometimes all these symptoms are present, and constitute an autistic syndrome.

� The various studies carried out among the autists show that 5 to 7 % autists are Fragile Xq.



253

o In the female: The mental retardation is mild or absent. They can present with: school difficulties (less than in the boy), memory disorders, changing mood, timidity, relational difficulties, and depressive tendency. These symptoms are often misinterpreted for social causes. • IV. Diagnosis: the karyotype can show

recurrent gaps in Xq27-q28; however, the diagnosis now rely on the molecular study of the genes.

FRAXA • The disease is due to the hyperexpansion of a

CGG trinucleotide repeats in the 5' untranslated region of the gene FMR-1 (fragility, mental retardation), located in Xq27.3.

• As a consequence of their hyperexpansion, these CpG islands become hypermethylated, leading to shut down the FMR-1 gene expression.

• The normal FMR-1 product is a protein called FMRP, a RNA binding protein widely expressed, in particular in the brain and the testis

• In the normal population, the CGG repeat size is variable, from 6 to 54 repeats; it is inherited in a stable manner.

• Some people have between 60 and 200 repeats; this is called premutation; it is inherited in an unstable manner (you tend to have more repeats than Mummy), but stable in the individual (identical in each cell). Premutation carriers have a

normal phenotype. Frequency of premutations in the population is 2.5/1000.

• Hyperexpansion of more than 200 repeats are called full mutation ; they are hypermethylated (on cytosines; even on the active X); it is inherited in an unstable manner, but also, the mutation is unstable in the individual (somatic mutations).

• Almost all males and half of females with the full mutation exhibit the syndrome. It is milder in females.

Notes: • Passage from the normal allele to premutation

as never been observed. • Passage from premutation to mutation

(unstability, or expansion through inheritance) is only through transmission from a female carrier.

FRAXE • Locus in Xq27-q28, 600kb distal to FRAXA. • Identical process of hyperexpansion of CpG

islands. • Much milder phenotype. Note: this type of unstable mutations has been found in other diseases, such as Huntington disease, a progressive neuropsychiatric disorder with CAG repeats in 4p16.

D - 47, XXX

• Epidemiology: 1 / 1 000 female births; increased parental age.

• Clinics:

o Often undetected: a normal female with normal phenotype, puberty, fertility, and offspring (most often).

o Precocious menopause. o Mild mental delay and/or psycho-

social disturbances are sometimes found.



254

E - 48, XXXX and 49, XXXXX

• Mimics trisomy 21; mental retardation.

F - 47, XYY

• Epidemiology: 1 / 1 000 male births. • Clinics: o Often undetected: a normal but tall

male with a normal phenotype. o Fertility may be reduced; normal

offspring. o Mild mental delay can be present;

impulsivity, violence, and psychiatric behaviour are not rare.

G - XX MALE SYNDROME

• Epidemiology: 0.1 / 1 000 male births. • Clinics: Klinefelter like phenotype; sterility. • Sex reversal can be due to the presence of

male determining sequences on a X chromosome (from a X/Y interchange at paternal meiosis), or on an autosome (from a Y/autosome translocation in the father), in particular SRY (Sex determining Region, Y chromosome). Other sex determining genes, usually sitting on gonosomes or on autosomes are likely to be involved.

H - XY FEMALE SYNDROME

• Epidemiology: 0.1 / 1 000 female births. • The phenotype is that of a female with ovarian

failure, and with or without other stigmata (e.g. sexual anomalies, limbs anomalies).

• Sex reversal in XY females can be due to mutations in SRY in 15%, or to other known or unknown genes mutations; some of these genes map to autosomes (e.g. SOX9 on chromosome 17).

I - NOONAN SYNDROME

• Formerly called Turner syndrome with a normal karyotype (46, XX or 46, XY) from the

shortness and other common signs: this is why it is herein cited. It is in fact an autosomal dominant trait.

• Cardiac malformations, mild mental retardation, infertility or fertility.

• A gene maps in 12q24.

OTHER CHROMOSOME IMBALANCES

A - TRIPLOIDY

• Epidemiology: the most frequent chromosome aberration in early miscarriages; found in 20 % of spontaneous miscarriages. Stillbirths are also frequent; livebirth can occur, but the baby dies shortly afterwards.

• Karyotype: 3N = 69 chromosomes: i.e. 69, XXX, or 69, XXY, or rarely 69, XYY; due to a fertilisation anomaly: digyny: non-expulsion of the 2nd polar body; or diandry: fertilisation of 1 oocyte I by 2 spermatozoa. Diandry is 4 times more frequent than digyny.

• Clinics: Preeclampsia; large placenta, with frequent hydatiform mole; severe growth retardation; microcephaly; syndactily; heavy brain, heart, kidney and ocular malformations leading to death.

B - TETRAPLOIDY

4N = 92 chromosomes. Found in 5 % of miscarriages. Literature records very few live births, but with death soon after.


Huret JL, Léonard C. Other Constitutional Chromosome Diseases. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4):248-254.



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