cytogenomics of cancers from chromosome to sequence

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2ava i lab le at www.sc ienced i rec t . com

www.e lsev ie r . com/ loca te /moloncReview

Cytogenomics of cancers: From chromosome to sequenceAlain Bernheim*

Laboratoire de Genomique Cellulaire des Cancers, INSERM U985 and Molecular Pathology, Biopathology Department, Institut de Cancerologie

Gustave Roussy, 39 rue Camille Desmoulins, 94805 Paris-Villejuif Cedex, FranceA R T I C L E I N F O

Article history:

Received 20 May 2010

Accepted 2 June 2010

Available online 11 June 2010

Keywords:

Cancer

Chromosome abnormalities

Cytogenetics

Oncogenesis* Tel.: 33 (0) 1 42 11 47 79; fax: 33 (0) 1 4E-mail address: [email protected]

1574-7891/$ e see front matter 2010 Federdoi:10.1016/j.molonc.2010.06.003A B S T R A C T

The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tu-

mor progression is now well established. These alterations are multiple and diverse and

the products of these rearranged genes play an essential role in the transformation and

growth of cancer cells. The validity of this assumption is demonstrated by the development

of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these

changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting

drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal

abnormalities is becoming an essential contribution to the diagnosis and prognosis of can-

cers but also for monitoring minimal residual disease or relapse. The concept of the cyto-

genetic uniqueness of each cancer has resulted in personalized treatment. This

investigation will expound upon, besides the recurrent genomic alterations, the numerous

products of perverted Darwinian selection at the cellular level.

2010 Federation of European Biochemical Societies.Published by Elsevier B.V. All rights reserved.1. Introduction malignancy-specific (hematological or mesenchymal malig-The Boveri hypothesis (Boveri, 1914) that cancer could be

a chromosomal disease (Balmain, 2001) of the cell genome

has been widely demonstrated by the cytogenetics and geno-

mics of malignant diseases during the last fifty years. The

seminal observations of the Ph chromosome in CML (Nowell

and Hungerford, 1960; Rowley, 1973) and the correlation be-

tween doubleminute chromosomes and genetic amplification

are examples of how fruitful this approach has been. Acquired

andmonoclonal characteristics of most malignancies and the

clonal evolution of tumor cell populations were described by

cytogeneticists before the era of chromosome banding. Spe-

cific chromosomal rearrangements, mainly translocations

were described by banding and were found to be2 11 52 60.

ation of European Biochenancies). Due to their presence in various cell types in bone

marrow, they allowed us to demonstrate the coexistence of

normal and malignant cells in the same tissue and led to the

hypothesis of stem cell involvement in several malignancies

(e.g. MDS or CML). Using the Ph chromosome as a marker of

malignant cells, it was possible to show that it was present

in all myeloid cells including B lymphocytes (Bernheim

et al., 1981b).

The recurrent breakpoints found in translocations in leu-

kemia and lymphoma were enigmatic when gene mapping

was in its infancy. The observation of variant translocations

in Burkitts lymphoma allowed us to hypothesize that the spe-

cific breakpoint of this proliferation was located on 8q24

(Bernheim et al., 1981a), near a transforming gene (Lenoirmical Societies. Published by Elsevier B.V. All rights reserved.

mailto:[email protected]/locate/molonchttp://dx.doi.org/10.1016/j.molonc.2010.06.003http://dx.doi.org/10.1016/j.molonc.2010.06.003http://dx.doi.org/10.1016/j.molonc.2010.06.003http://dx.doi.org/10.1016/j.molonc.2010.06.003

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2310et al., 1981), because the term oncogenewas too precise to be

used at the time. The correlation between the localization of

the immunoglobulin genes on chromosomes 14, 2 or 22 and

the 8q24 factor allowed us to put forward the hypothesis of

a position effect due to the translocation of a promoter from

the immunoglobulin gene to a transforming agent (Frohling

and Dohner, 2008; Huret, 2010; Lenoir et al., 1982). Cytogenet-

ics, molecular biology and gene mapping paths then con-

verged and the following year enabled the identification of

theMYC gene in Burkitts lymphoma. ThisMYC genewas dys-

regulated by an immunoglobulin enhancer of new genes. Dur-

ing the next twenty years, most recurrent balanced

breakpoints were cloned (Huret, 2010; Mitelman et al., 2007;

Rowley, 1998; Sandberg, 2002), whether they were dysregu-

lated genes such as BCL2 in follicular lymphoma, or chimeric

ones. Most of the important genes in malignancies were thus

identified. This task continues to be a major issue, as we are

well short of exhaustive knowledge of the somatic genetic al-

terations in malignancy. These results radically changed our

view of cancer. The abnormal chromosomes could often be

qualified as markers of malignancy as they were observed

exclusively in malignant cells. Their presence enhanced the

quality of the diagnosis and allowed a clearer definition of

the prognosis. Several diagnoses have become a routine

task. Exquisitely sensitive procedures are used to detect and

quantify residual disease. All types and sizes of chromosomal

abnormalities can be found in all cancers (Fagin, 2002; Huret

et al., 2001; Mitelman et al., 2003). More than 54,000 patients

are reported in the Mitelman Catalog (Mitelman et al., 2003)

and the WHO (World Health Organization) includes a growing

number of genomic rearrangements in the definition ofmalig-

nancies. More importantly, the products of these mutated or

dysregulated genes have become the highly specific targets

of new drugs (Druker, 2008; Thompson, 2009) which are radi-

cally different from conventional chemotherapy.2. Origin of chromosomal rearrangements in cancer

The human genome of a cell is far from stable. Chemical alter-

ations, viral aggressions and ionizing radiations are ubiqui-

tous. The process of replication is not absolutely faithful nor

is chromosomal segregation at mitosis (even meiosis is not

accurate due to gametic malsegregation: more than 60% of

zygotes will have a chromosomal abnormality that will lead

to an early abortion, which will mostly go unnoticed).

In somatic cells, partial failure is the rule andnot the excep-

tion. Fresh cells are constantly generated from stem cells and

damagedcellsareeliminated.Overall control is thusadynamic

process with multiple checkpoints at cellular and organism

levels via homeostasis and immunological processes. The

actual hypothesis of tumorigenesis is a mutation (including

chromosomal rearrangements) (Schvartzman et al., 2010)

that confers a selective advantage on a dividing cell. The

monoclonal proliferation will be exposed to new mutations

with a new round of selection (Gisselsson, 2001). The recursive

multi-stage process will culminate with a significant tumor

that will exhibit invasive and metastatic properties and often

considerable clinical aggressiveness. This perverted Darwin-

ian selection at the cellular level probably acts on larger cellpopulations than evolution on whole individuals in nature

and the time required for the generation process is shorter.

However, as tumordevelopment is theexceptionandgenerally

occurs late in life, the process is poorly efficient and this is also

due to very tight controls. Immunology plays a major role, as

suggested by the frequency of Burkitts lymphoma or Kaposis

sarcoma in AIDS patients.

In several benign tumors such as lipoma (Mandahl, 2000) or

uterus leiomyoma (Lynch and Morton, 2007) specific clonal

chromosomal abnormalities can be observed. This suggests

that all genomic rearrangements found in tumors, dont give

complete proliferative dysregulation, neither invasive and

metastatic characteristics.

Hereditary deficiencies in repair processes such as in Xero-

derma Pigmentosum, Fanconi anemia (Moldovan and

DAndrea, 2009) and other chromosomal instability syn-

dromes, often characterized by chromosomal breakages, are

characterized by high level malignancies.

Irradiation produces chromosomal breakage aswell asmu-

tations and is known to be a potent mutagen. Numerous

chemicals are clastogenics including free radicals, of various

origins such as a chronic inflammation.3. Chromosomal rearrangements

Several chromosome rearrangements (Albertson et al., 2003)

are very specific and observed only in a particular disease

(Mitelman et al., 2003). The translocations found in leukemias,

lymphomas, sarcomas and some carcinomas belong to this

category (Tables 1 and 2). They participate in the definition

of the disease under the term genetic, as in the recent classi-

fications of the WHO (Swerdlow et al., 2008). Other chromo-

somal abnormalities simply indicate a cellular malignant

process such as isochromosomes 8q and 17q in carcinomas

(Huret, 2010) or trisomy 8 in acute myeloblastic leukemia

(Huret, 2010). The pattern is a set of chromosomal abnor-

malities that have no meaning when isolated, but is more or

less associated with the diagnosis. Conventional chromo-

somal abnormalities are only the tip of the iceberg. Many al-

terations are too small to be seen by conventional

techniques or even because mitosis are lacking, as in most

solid tumors.4. From cytogenetics to cytogenomics

As the human genome has been completely sequenced, genes

along the 46 human chromosomes, which are conventionally

known according to their appearance at the fleeting stage of

mitosis duringmetaphase,with two clearly visible chromatids

attached to centromeres and capped by a telomere, are now

completely mapped. During interphase, the chromosomes

are classically indistinct in the cell nucleus. The FISH painting

technique has revealed that they maintain their individuality

as chromosome territories. The position of the genes in these

territories also seems to be important for their expression. A

gene is inactive in an internal position, whereas a gene is ac-

tive at the periphery or outside the territory.

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Table 1 e Selected chromosomal abnormalities in hematological malignancies.

Disease Chromosomalabnormalities

Genesa Type Targetedtherapyb

Acute malignant iymphoid proliferation

ALL L1/L2 Pre-B t(1;19)(q23;p13) PBX1-TCF3 I

ALL L1/L2 B or biphenotypic t(9;22)(q34;q11) ABL-BCR I

ALL L1/L2 biphenotypic t(4;11)(q21;q23) AF4-MLL I

ALL L1/L2 (child) t(12;21)(p13;q22) TEL-AML1 I

ALL L1/L2 50e60 chromosomes,

hyper diploidy

III

ALL L1/L2 t(5;14)(q31;q32) IL3*IGH II

ALL L1/L3 dup(6)(q22eq23) MYB III

ALL L1/L2 del(9p),t(9p) ?CDKN2(p16) IV

ALL L1/L3 del(9)(p13) PAX5 IV

ALL L1/L2 t(9;12)(q34;p13) ABL-TEL I

ALL L1/L2 t(11;V)(q23;V) MLL-V I

ALL L1/L2 del(12p) ETV6? IV

ALL L1/L3 episome(9q34.1)x NUP214-ABL1 I ImatinibB (ALL3, Burkitts leukemia/lymphoma) t(8;14)(q24;q32) IGH*MYC II

B (ALL3, Burkitts leukemia/lymphoma) t(2;8)(p12;q24) IGK*MYCc II

B (ALL3, Burkitts leukemia/lymphoma) t(8;22)(q24;q11) IGK*MYCc II

Follicular lymphoma to large-cell diffuse

lymphoma

t(14;18)(q32;q21) and

variants

IGH*BCL2/IGK/IGL II

Mantle-cell lymphoma t(11;14)(q13;q32) CCND1*IGH II

Marginal zone lymphoma t(1;14)(p21;q32) BCL10*IGH II

Marginal zone lymphoma 3 III

Marginal zone lymphoma t(11;18)(q21;q21) BIRC3-MALT1 I

Large-cell diffuse lymphoma t(3;14)(q27;q32), variants BCL6*IGH, BCL6*V II

Large-cell diffuse lymphoma t(11;14)(q13;q32) CCND1*IGH II

Anaplastic large-cell lymphoma t(2;5)(p23;q35), variants ALK-NPM1 I

Chronic malignant lymphoid proliferation

Lymphocytic B cell lymphoma, chronic

lymphocytic leukemia

t(11;14)(q13;q32) CCND1*IGH II



t(14;19)(q32;q13) IGH*BCL3 II



t(2;14)(p13;q32) BCL11A*IGH II



del(11)(q23.1) ATM IV



del(13)(q14) DLEU, miR-16-1 & 15a IV

Prolymphocytic T leukemia inv(14)(q11q32) TCRA/TCR D* TCL1A II

Prolymphocytic T leukemia t(14;14)(q11;q32) TCRA/TCR D* TCL1A II

Prolymphocytic T leukemia t(7;14)(q35;q32.1) TCRB* TCL1A II

Multiple myeloma t(11;14)(q13;q32) CCND1*IGH II

Multiple myeloma t(4;14)(p16;q32) WHSC1-IGHG1 II

Multiple myeloma del(6)(q21) IV

del(13)(q14) DLEU, miR-16-1 & 15a IV

Acute myeloid leukemia, myelodysplastic

syndrome

AML M2 t(8;21)(q22;q22) RUNX1-RUNX1T1 I

AML M3 and microgranular variant t(15;17)(q22;q11e12) PML-RARA I Retinoid Acid

AML M3 (atypical) t(11;17)(q23;q12) PLZF-RARA I Retinoid Acid

AML M4Eo inv(16)(p13q22) ou CBFB-MYH11 I

t(16;16)(p13;q22 CBFB-MYH11 I

AML M5a and other AML t(9;11)(p22;q23) MLL-MLLT3 I

AML M5a and other AML t(11q23;V) MLL multiple partners

including MLL

I

Acute megakaryoblastic leukemia t(1;22)(p13;q13) RBM15-MKL1 I

AML, MDS t(3;3)(q21;q26) or variants RPN1-EVI1 I

AML, MDS t(3;5)(q25;q34) MLF1-NPM1 I

AML, MDS t(5;12)(q33;p13) PDGFRB-ETV6 I

AML, MDS 5/del(5q) RPS14 IVAML, MDS t(6;9)(p23;q34) DEK-NUP214 I

(continued on next page)

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2 311


Table 1 (continued)

Disease Chromosomalabnormalities

Genesa Type Targetedtherapyb

AML, MDS t(7;11)(p15;p15) HOXA9-NUP98 I

AML, MDS 7 ou del(7q) Numerous genes IVAML, MDS 8 IIIAML, MDS t(8;16)(p11;p13) MOZ-CBP I

AML, MDS t(9;12)(q34; p13) ETV6-ABL I

AML, MDS t(12;13)(p13;q12.3) ETV6-CDX2 I

AML, MDS t(12;22)(p13;q13) ETV6-NM1 I

AML, MDS t(12;V)(p13;V), del(12p) ETV6L-V I

AML, MDS t(16;21)(p11;q22) FUS-ERG I

AML, MDS del(20q) IV

Therapy-induced leukemia

Alkylating agent- and

irradiation-induced leukemia

5 ou del(5q) IV

Alkylating agent- and

irradiation-induced leukemia

7 ou del(7q) IV

Anti topoisomerase

II induced leukemia

t(11q23;V) MLL-V I

Chronic myeloid proliferation

Chronic myeloid leukemia (CML) t(9;22)(q34;q11) BCR-ABL1 I Imatimib, 2nd generation TKI

Lymphoblastic acutisation of CML t(9;22), 8,Ph, 19, i(17q) BCR-ABL1 I & III Imatimib, 2nd generation TKIPolycytemia vera 9p IIIPolycytemia vera del(20q) IV

MDS/MPD t(8;9(p21;p24) PCM1-JAK2 I

Chronic myelomonocytic leukemia t(5;12)(q33;p13) PDGFRB-TEL I Imatinib

5q- syndrome del(5q) RPS14 IV

a * dysregulation gene, -mean fusion gene, V rearrangement variants. For details see: http://atlasgeneticsoncology.org.b Targeted therapy against genes involved in genetic rearrangements.

c miR-1204 and miR-1205 could also be dysregulated (Toujani et al., 2009).

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2312A gene-rich chromosome such as chromosome 19 seems to

fit into an internal position in the nucleus, whereas those lack-

ing in genes are at the nuclear periphery, forming a protection

against possible aggression mutagens. It is conceivable that

the structural organization of chromosomes in the cell nu-

cleus will become a major subject of study in the near future

(Mani et al., 2009; Nikiforova et al., 2000).

The emergence of molecular cytogenetics (Pleasance et al.,

2010), whose main methods are in situ hybridization (FISH),

comparative genomic hybridization (aCGH), and now whole

genome sequencing, possibly associated with DNA stretching

techniques (DNA combing) and chromosomemicrodissection,

has greatly expanded the cytogenetics field metamorphosing

it into cytogenomics (Beroukhim et al., 2010; Bignell et al.,

2007).5. In situ hybridization (ISH)

The molecular reassociation of chromosomal DNA with DNA

probes in situ can be done at all stages of the cell cycle. Chem-

ical labeling is now very diverse, allowing the detection of

probes by fluorescence or increasingly by cytochemistry. Of-

ten available commercially, these reagents cover a continu-

ously growing spectrum of chromosomal rearrangements

that are detected onmitotic chromosomes but also on cell nu-

clei. Consequently, cytogenetic analysis is not limited to suc-

cessful cell cultures. Adaptations are successfully done onparaffin sections, especially to detect gene amplification

such as ERBB2-NEU, but also for single copy rearrangements.

The human genome sequence, available on the Internet, of-

fers tremendous opportunities to cytogeneticists as they can

order probes next to a breakpoint, making investigations by

FISH available for the entire genome.

The use of three simultaneous florescence stains, one to la-

bel each of the two probes and one for DNA staining, is now

commonplace. Currently five fluorochromes are typically

available to create more than 24 different color combinations

simultaneously (SKY, multifish) that identify each chromo-

some. The fluorescencemicroscope is nowpart of a computer-

ized imaging system with automated scanning, ergonomic

reading solutions and quality control which is necessary for

clinical practice and incorporates these advances.6. CGH

CGH(ComparativeGenomicHybridization)quantifies testDNA

compared to control DNA, and this can be done at any point in

the genome. Initially described by Kallioniemi et al. (1992), its

principle is simple.ThepurifiedtumorDNAismarkedbyafluo-

rochrome emitting in green (e.g., fluorescing), whereas normal

DNA ismarkedby another fluorochrome emitting in the red (or

vice versa). Originally both DNAwere cohybridized on awhole

normal human genome, represented by normal humanmeta-

phasic chromosomes, according to FISH procedures. The

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Table 2 e Selected examples of chromosomal rearrangements in solid tumors.

Disease Chromosomalrearrangements

Genea,b Type Targetedtherapyc

Breast cancer amp(1)(q32.1) IKBKE IIIa

Breast and various cancers amp(6)(q25.1) ESR1 IIIa Tamoxifen

Breast cancer amp(17)(q21.1) ERBB2 (HER2) IIIa Trastuzumab, Lapatinib

Breast cancer amp(20)(q12) NCOA3 IIIa

Breast and various cancers t(12;15)(p13;q25) ETV6-NTRK3 I

Colon cancer del(4)(q12) REST IV

Colon cancer del(5)(q21eq22) APC IV

Hepatocellular carcinoma amp(11)(q13eq22) BIRC2 IIIa

Hepatocellular carcinoma amp(11)(q13eq22) YAP1 IIIa

Lung cancer amp(1)(p34.2) MYCL1 IIIa

Lung cancer (non-small-cell) inv(2)(p22ep21p23) EML4-ALK I

Lung, head and neck cancers amp(3)(q26.3) DCUN1D1 IIIa

Lung cancer (non-small-cell) amp(7)(p12) EGFR IIIa Cetuximab, Panitumumab, Gefitinib, Erlotinib

Lung cancer (non-small-cell) amp(14)(q13) NKX2-1 IIIa

Ovarian cancer amp(1)(q22) RAB25 IIIa

Ovarian cancer amp(3)(q26.3) PIK3CA IIIa

Ovarian, breast cancers amp(11)(q13.5) EMSY IIIa

Ovarian, breast cancers amp(17)(q23.1) RPS6KB1 IIIa

Prostate cancer amp(X)(q12) AR IIIa

Prostate cancer del(21)(q22.3q22.3) TMPRSS2*ERG II

Renal carcinoma papillary .7q31 METRenal carcinoma papillary .7q31 METRenal carcinoma papillary .17q ?Renal carcinoma papillary .17q ?Renal carcinoma papillary t(X;1)(p11;p34) PSF-TFE3

Renal carcinoma papillary t(X;1)(p11.2;q21.2) PRCC-TFE3

Thyroid cancer follicular t(2;3)(q12eq14;p25) PAX8-PPARG I

Thyroid cancer papillary inv(10)(q11.2q11.2) RET-NCOA4 I

Thyroid cancer papillary inv(10)(q11.2q21) RET-CCDC6 I

Ewings sarcoma t(11;22)(q24.1eq24.3;q12.2) FLI1-EWSR1 I

Ewings sarcoma t(21;22)(q22.3;q12.2) ERG-EWSR1 I

Rhabdomyosarcoma (alveolar) t(1;13)(p36;q14) PAX7-FKHR I

Rhabdomyosarcoma (alveolar) t(1;13)(p36;q14) PAX7-FKHR I

Rhabdomyosarcoma (alveolar) t(2;13)(q37;q14) PAX3-FKHR I

Chondrosarcoma (extrasqueletical) t(9;17)(q22;q11) RBP56-CHN I

Chondrosarcomas (myxoid) t(9;22)(q22;q12) EWS-CHN I

Desmoplastic tumors t(11;22)(p13;q12) WT1-EWS I

Clear cell sarcomas t(12;22)(q13;q12) ATF1-EWS I

Liposarcomas t(12;16)(q13;p11) CHOP-FUS I

Liposarcomas (myxoid) t(12;16)(q13;p11) CHOP-FUS I

Dermatofibrosarcomas protuberans t(17;22)(q22;q13) COL1A1-PDGFB I

Alveolar soft part sarcomas der(17)t(X;17)(p11;q25) ASPSCR1-TFE3 I

Synovialosarcomas t(X;18)(p11.2;q11.2) SYT-SSX1/SSX2-SYT I

Malignant melanoma amp(3)(p14.2ep14.1) MITF IIIa

Glioma amp(1)(q32) MDM4 IIIa

Astrocytoma, glioblastoma .7 ? IIIAnaplastic oligodendroglioma del(19q) ? IV

anaplastic oligodendroglioma del(1p) ? IV

Medulloblastoma amp(2)(p24.1) MYCN IIIa

Medulloblastoma del(6)(q23.1) WNT IV

Medulloblastoma amp(8)(q24.2) MYC IIIa

Medulloblastoma del(9)(p21) CDKN2A/CDKN2B IV

Medulloblastoma i(17q) p53 III, IV

Neuroblastoma amp(2)(p24.1) MYCN IIIa

Neuroblastoma amp(2)(p23.1) ALK IIIa

Neuroblastoma del(1p) ? IV

Renal-cell cancer del(3p26ep25) VHL IV

Retinoblastoma del(13)(q14.2) RB1 IV

Retinoblastoma amp(1)(q32) MDM4 IIIa

Retinoblastoma del(13)(q14) RB

Testicular germ-cell tumor 12p ? IIITesticular germ-cell tumor 12p ? IIIWilms tumor del(11p) WT1 IV

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M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2 313


Table 2 (continued)

Disease Chromosomalrearrangements

Genea,b Type Targetedtherapyc

Wilms tumor del(X)(q11.1) FAM123B IV

Various cancers 1q ? IIIVarious cancers 1q ? IIIVarious cancers del(3p) ? IV

Various cancers amp(5)(p13) SKP2 IIIa

Various cancers amp(5)(p13) SKP2 IIIa

Various cancers amp(6)(p22) E2F3 IIIa

Various cancers del(6q) ? IV

Various cancers amp(7)(p12) EGFR IIIa Cetuximab, Panitumumab, Gefitinib, Erlotinib

Various cancers amp(7)(q31) MET IIIa

Various cancers amp(8)(p11.2) FGFR1 IIIa

Various cancers amp(8)(q24.2) MYC IIIa

Various cancers del(9)(p21) CDKN2A/CDKN2B IV

Various cancers del(10)(q23.3) PTEN IV

Various cancers amp(11)(q13) CCND1 II, IIIa

Various cancers del(11)(q22eq23) ATM IV

Various cancers del(11q) ? IV

Various cancers amp(12)(p12.1) KRAS IIIa

Various cancers amp(12)(q14.3) MDM2 IIIa

Various cancers amp(12)(q14) CDK4 IIIa

Various cancers amp(12)(q15) DYRK2 IIIa

Various cancers amp(13)(q32) GPC5 IIIa

Various cancers 17q ? IIIVarious cancers amp(17)(q21.1) ERBB2 (HER2) IIIa Trastuzumab, Lapatinib

Various cancers del(17)(p13.1) TP53 IV

Various cancers del(17)(q11.2) NF1 IV

Various cancers amp(19)(q12) CCNE1 IIIa

Various cancers amp(20)(q13) AURKA IIIa

a a* dysregulation gene, -mean fusion gene, V rearrangement variants. For details see: http://atlasgeneticsoncology.orgb Often also mutated.

c Targeted therapy against genes involved in genetic rearrangements.

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2314unique chromosome sequences were simultaneously the tar-

getsof the tumorandcontrolDNAs.Afterwashingandbanding

withDAPI to generate banding, preparationswere analyzed on

amicroscopicdigital imageanalyzer.Nowthe targetsareavery

largenumber of BACsor of selectedoligonucleotides, sampling

the total human genome (Pinkel and Albertson, 2005).

The hybridization of tumor DNA to each point of the ge-

nome is compared to that of control DNA. A loss of this region

in the tumor genomewill be revealed by an excess signal from

the normal DNA. Conversely, a gain will be detected by an ex-

cess of tumorDNA,whichwill bemajor in the case of gene am-

plification. The exact quantification is done by calculating the

normalizedratiobetweentumorandnormalDNAfluorescence

along each chromosome. Metaphasic chromosomes are cheap

natural microchips covering the entire genome with a high

level of integration, but with poor resolution. 1 Mb resolution

has been achievedwith BAC CGH arrays. Now, oligonucleotide

chipswithin the resolution rangeof a fewkb, from1 105 up toseveral million, are available and yield robust results.

Paradoxically, CGH greatly simplifies the interpretation of

anomalies in its standard format.

Tumor DNA can be prepared from fresh or frozenmaterial.

CGH is very sensitive to the presence of normal cells in the

sample under analysis, which exert a dilution effect on tumor

DNA. This makes CGH unreliable when there are fewer than

60% of normal cells. Enrichment in tumor cells could bedone by cell sorting or laser microdissection, but it would

probably be difficult to generalize those techniques.

CGHcannotdetect balanced translocations and their equiv-

alents, nor overall changes in ploidy (triploidy, tetraploidy).

The analysis can be far from simple in some cancers, with

the added complexity from inherited CNV. These CNV add

complexity to interpretation. However, the simplest way to

avoid it is tousenormalDNAfromeachpatient as controlDNA.

An alternativemethodology is single copy number analysis

derived from SNP analysis. This approach depicts the loss of

heterozygozity (LOH) which occurs via acquired isodisomy,

without copy number variation. The incidence reported is

about 10% of CNA (copy number aberration). Currently, there

is no system allowing the two analyses to be conducted rou-

tinely on the same array in cancer.7. Sequence

Next generation sequencing is rapidly progressing (Mardis,

2009). Prices are dropping every year, making the objective

of 1000$, or even less, for a full human genome fully conceiv-

able. Bioinformatics is very demanding but this aspect will be

solved in a few years. The first results of whole genome se-

quencing (WGS) in tumors revealed that the diagnosis of bal-

anced rearrangements could be achieved in the absence of

http://atlasgeneticsoncology.orghttp://dx.doi.org/10.1016/j.molonc.2010.06.003http://dx.doi.org/10.1016/j.molonc.2010.06.003http://dx.doi.org/10.1016/j.molonc.2010.06.003

e MET

nce

r,MYCN

in

blastoma

rmutationofRB,loss

of

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2 315classic karyotypes that require cell culture. Several malignan-

cies have recently been sequenced. Extremely divergent

results have been obtained. Several solid tumors exhibit

a very high number of mutations, up to more than 20,000,

a similar number to that of genes (Pleasance et al., 2010). In

contrast, AML, with a normal karyotype, exhibits a few muta-

tions, most of which are in known oncogenes (Mardis et al.,

2009).Table

3e

Chromosometypology

abnorm

alities.

Abnorm

ality

type

Involvedgenes

Main

functionaleffect

Exampl

TypeI

Fusiongenesoriginating

from

transloca

tionsoroth

er

chro

moso

malrearrangements

Onco

genes,

kinase

s,

transc

riptionfactors,etc

Functiongain

FLI1-EW

Sin

thet

(11;22),MLLduplica

tion

TypeII

Positioneffect

originatingfrom

transloca

tionsoroth

er

chro

moso

malrearrangements

Onco

genes,

oth

ergenes

Dysregulation

IGH*BCL2in

t(14;18),MYCin

t(8;14)(q24;q32)

TypeIII

Copynumbergain

ofallorpart

ofach

romoso

me

(IIIs)

Onco

genes,

oth

ergenes

Genedosa

ge

effect

(mayact

ona

modifiedgene)

Duplica

tionofth

ePhin

CML,of

genebywhole

trisomy

7orse

gmentalduplica

tion

TypeIIIa

Geneamplifica

tion

(more

than2,2e4co

py

perhaploid

genome

Onco

genes,

oth

ergenes

Genedosa

geeffect

(sometimesactingon

amodifiedgene)

EGFRin

lung

cance

r,ERBB2/H

ER2in

breast

ca

neuro

blastom

a

TypeIV

Totalorpartial(IVs)

loss

ofach

romoso

me,Total

orpartialacq

uiredisodisomy,inactivationbymutation.

Tumorsu

ppressorgenes

Loss

offu

nction,LOH

InactivationofRBgenein

retino

via

deletionofch

romoso

me13o

CDKN2A

invariousca

nce

rs8. Typology of genomic abnormalities (chromosomeand gene) (Table 3)

Chromosomal abnormalities can be classified into four types,

depending on their consequences.

Type I refers to the generally balanced translocations or

other structural rearrangements that fuse two genes, form-

ing a hybrid gene. As the structure of eukaryotic genes is di-

vided into exons and introns, this fusion enables the

formation of chimeric proteins which acquire an oncogenic

potential. This new hybrid gene is malignancy-specific as

for example the FLI1-EWS fusion gene following the t(11;

22) (q24, q12) translocation in Ewings sarcoma (Delattre

et al., 1992, 1994; Riggi and Stamenkovic, 2007) or the

EML4-ALK fusion gene following an inversion on 2p in lung

carcinoma (Soda et al., 2007) (Tables 1 and 2). These anom-

alies may be regarded as resulting in, strictly speaking,

a gain of function. The genes involved often involve tran-

scription factors but also tyrosine kinases. These often bal-

anced abnormalities first appeared to be mainly confined

to hematological malignancies and sarcomas but they are

now often found in carcinomas. Anomalies of RET or of

the PAX8-PPARG fusion gene in thyroid cancer (Nikiforova

and Nikiforov, 2009; Pierotti, 2001), the t(X;1) translocation

in cancers of the kidney (Argani et al., 2003; Camparo

et al., 2008), the inv(2)(p21p23) fusing EML4 to ALK in lung

cancers are good examples (Table 3). Cryptic genomic rear-

rangements may contribute to gain of function: partial du-

plication of a gene on itself as in MLL with the 50 part issometimes duplicated and activates this gene in leukemia

secondary to chemotherapy with topoisomerase II inhibitors

(Huret, 2009).

The chromosomal balanced translocations, which give

rise to chimeric genes, are often malignancy-specific and

are still the main road to identifying the genes involved in

cancer through positional cloning. Although a lot of rear-

rangements are now well known, other less frequent ones

have yet to be investigated in detail as they could help

identify new genes. Several of the genes involved in fusion,

are swingers as they can be associated with many other

partner genes such as RET for example in thyroid cancer.

The processes are recurrent as these partner genes are

sometimes themselves associated with various partners.

This concept of networking between various oncogenes,

coupled with the fact that there are only 23,000 genes in

humans, suggests that a limited number of genes are in-

volved in oncogenesis.

Type II concerns the case of dysregulation of a gene by

position effect. The paradigm is Burkitts lymphoma charac-

terized by the t(8;14) (q24, q32) or its variant, t(2; 8) (p12; q24)


M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2316


M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2 317or t(8; 22) (q24, q11) (Bernheim et al., 1981a). The MYC gene,

localized to 8q24, is dysregulated under the influence of an im-

munoglobulin heavy chain gene enhancer localized in 14q32.

The same mechanism is thought to occur in variant forms

with kappa (2p12) or lambda (22q11) light chains despite the

distant 30 breakpoint of MYC and the possible involvement ofmiRNA (Figure 1) (Toujani et al., 2009). The MYC gene remains

structurally intact, although it is the target of numerous punc-

tual mutations. As it occupies the position of the variable part

of the immunoglobulin genes, like them, it is submitted to

hypermutation possibly induced by AID. These translocations

on immunoglobulin geneshavebeena real key to thediscovery

of a number of important genes such as BCL1 and BCL2. Iso-

lated from the t(14; 18) (q32, q21) which is specific for non-

Hodgkin centro-follicular lymphoma, BCL2 is a ubiquitous ap-

optosis inhibitor.

Type III, is the gain of genetic material.

The gain of material is very frequent and may involve

whole chromosomes as the result of malsegregation gener-

ated by a pathological spindle. Segmental gains result from

unbalanced structural chromosomal rearrangements. Their

functional significance remains unknown but an increase in

gene size with a gain of function is often seen. For example,

the MET oncogene is overrepresented in sporadic papillary re-

nal-cell tumors via a trisomy 7 and the protein is proportion-

ally overexpressed. During acutisation in Chronic Myeloid

Leukemia (CML), the Ph chromosomewith the BCR-ABL fusion

gene, is often duplicated. Copy number abnormalities are very

often segmental due to structural unbalanced chromosomal

rearrangements such as the gain of part of 17q in

neuroblastomas.

Type IIIa corresponds to gene amplification which is a se-

lective increase in DNA copy number (Sartorius). It can ex-

hibit two cytogenetic aspects. Double minute (DM)

chromosomes are self-replicating extra-chromosomal acen-

tric rings or episomes that were initially shown in meta-

phase and are now easily found in interphase cells.

Generally, there is considerable heterogeneity from cell to

cell in the number of DM, even if the mean number is

high. In some instances, the DM can be expulsed from the

nucleus and even from the cell (Valent et al., 2001). The

other aspect of gene amplification is homogenously staining

regions (HSR) where multiple copies of a genomic region are

integrated into chromosome(s) in the form of block(s) of re-

peat amplicons. They are produced by a break-fusion-bridge

process that remains in the cycling process until the opti-

mal amount of gene expression is achieved. MYCN onco-

gene amplification in neuroblastoma which is oftenFigure 1 e Virtual cloning of 8q24 in Burkitt lymphoma showing MYC reg

Ly 47 cell lines, characterized by a t(8;22)(q24;q11), the der(8)t(8;22) region

chromosome 8 (labeled in green) appeared trisomic from pter to 8q24.2, 129

appeared normal (BL84 Partial profiling aCGH), corresponding to the nor

translocated to the der(22)(BL84 partial RHG-banding). The breakpoint wa

mir-1205 and mir-1206 (Toujani et al., 2009). The chromosome 22 (labele

modified. B) Then a complete loss of IGL (immunoglobulin light chain la

rearrangement of IGL, while the t(8;22) occurred during one of them. The

(immunoglobulin heavy chain) regions are also physiologically rearranged o

21.58e49.05 Megabases, the chromosome 22 is trisomic.observed in tumor cells as DM is generally observed as

HSR(s) in the culture-established cell lines generated from

these tumor cells. Some human cell lines however harbor

DM such as SW613 (Guillaud-Bataille et al., 2009), with

a MYC amplification linked to tumorigenesis in mice, but

also another population of DM derived from 14q24.1 that

were purported to contribute to maintaining amplification

in the form of DMs (Guillaud-Bataille et al., 2009).

The amplification can involve a series of oncogenes,

whose sequence does not appear to be impaired, such as

ERBB2, MYCN, MYC, CCND1, GLI, MDM2, ALK (Huret, 2010;

Santarius et al., 2010) but also gene fusion as in some alve-

olar rhabdomyosarcoma with the t(1;13) translocation

(Table 2). The number of copies of a DNA sequence that con-

stitute genome amplification is variously described but gen-

erally considered greater than 4-fold relative to a non-

amplified marker in a haploid genome. In diploid cells this

would be equivalent to at least 8 copies. For example, this

definition is used for MYCN amplification which is associ-

ated with a poor outcome in neuroblastoma (Schwab,

2004). ERBB2 amplification which is deemed present when

the mean FISH ratio of ERBB2_HER2 versus the centrometric

probe of chromosome 7, calculated after examining 60 cells,

is greater than 2 or if more than 6 copies/nucleus are found.

This is required to be eligible for anti-ERBB2 therapeutic

agents. Positive ERBB2-amplified cases are distinct from

cases that are equivocal for ERBB2 gene amplification

(Couturier et al., 2008). As the copy number in tissues is

measured extensively by array- or PCR-based techniques,

the criteria for genomic amplification are frequently

wrongly based on thresholds that are specific for the normal

experimental variations experienced, thus mixing gain and

real genetic amplification.

Type IV corresponds to the loss of genetic information, ei-

ther through deletion, unbalanced translocation, or any other

mechanism leading to the loss of heterozygosity (LOH), in-

cluding acquired parental unidisomy, be it complete or seg-

mental. Loss of function by point mutation is in this

category (Albertson et al., 2003; Chin and Gray, 2008). These

frequent rearrangements, diagnosed by the loss of heterozy-

gosity (LOH), losses of material by microarrays, FISH or karyo-

type, often involve tumor suppressor genes (e.g. RB, RET,

BRCA1, P53 genes) (Huret, 2010). They are involved in predis-

position to many types of cancer. Other losses of function

can affect genome repair genes, caretaker or gatekeeper

genes. These losses can affect non coding genes such as

miRNA that are non randomly lost in the same malignancy

(Calin and Croce, 2009; Croce, 2009).ion breakpoints (modified from Toujani et al., 2009). A) In BL84 and

harboring the MYC locus was duplicated. For example on BL84, the

.15 Megabases (BL84 partial RHG-banding), then its ratio on aCGH

mal chromosome 8 and to the distal part of the chromosome 8

s observed distal to MYC as expected and is mapped to PVT1, between

d in blue) from the centromere to the long arm telomere is first non

mbda) region is observed suggesting a physiological biallelic

IGK (immunoglobulin light chain kappa) and the IGH

n a single allele (A & B). After this lost region, from 22q11 to qter,


M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 23189. Evolution of chromosomal abnormalities intumors

Although the concept of primary abnormality and additional

anomalies is very important, it needs to be revisited. There

are numerous examples, such as leukemia, where a recurrent

chromosomal abnormality such as the t(9;22)(q34;q11) trans-

location in CML, was conjointly observed with the t(15;17)

(q22;q21) in promyelocytic AML. Only the t(9;22) was observed

after treatment. The two abnormalities were again present in

the same cells at relapse (Castaigne et al., 1984). Another ex-

ample is lymphomas, where a recurrent chromosomal abnor-

mality such as the t(8; 14)(q24, q32) translocation in Burkitts

lymphoma, is conjointly observed with the t(14;18) of follicu-

lar lymphoma (Tomita et al., 2009). This suggests that these al-

terations have cumulative effects, if not synergistic. They are

commutative, as the order in which they occur does not al-

ways appear to be important. In solid tumors, complex chro-

mosomal abnormalities reflect the multistep process of

oncogenesis and tumor progression. There are striking exam-

ples of profiles that show themultiple subclones in a single tu-

mor as for example in progression towards gene

amplification. Cell tolerance to alterations in the genome

means mayhem in genome maintenance. In some cases, the

alteration is exclusively local, with most of the chromosomes

exhibiting a normal profile. In others there are multiple rear-

rangements culminating in genomic storms with highly

rearranged chromosomal regions shown by aCGH. Telomeres

also appear to play a key role in controlling the number of cell

divisions, through gradual terminal truncation. The inactiva-

tion of this control introduces a form of chromosomal insta-

bility with telomeric fusions followed by random breaks

inducing cell death, but it may also select the cell with dam-

aged genomic material and allow it to recover telomerase

function (OSullivan and Karlseder, 2010). Cancer cell lines

with a highly rearranged karyotype can maintain stability

throughout the cell culture passages, which indicates that

rearranged chromosomes are not intrinsically unstable. It is

possible that the dynamic process of Darwinian selection of

the cancer genome leads to some form of stable pathologic

disease. Some tumors, that have amutator phenotype, exhibit

few visible chromosomal abnormalities.

The evolution of the chromosomal abnormalities is classic

during disease progression. It may occur as its natural history

such as the evolution of an indolent follicular lymphomawith

a single t(14;18) to an aggressive diffuse lymphoma with mul-

tiple abnormalities added to the initial translocation (Yunis

et al., 1989). A post-therapeutic relapse often keeps several

chromosomal rearrangements from the initial proliferation,

but some of the initial ones may be lost and new ones may

be acquired. This can lead to a search for residual disease

with wrongly targeted probes.10. Lesions and tumors secondary to physical orchemical mutagens

Alkylating agents or radiotherapy currently used to treat

cancers induce chromosomal breakage which is themanifestation of the genotoxic activity of such drugs. The

doses commonly used are in a range that allows tolerable

toxicity. Patients suffering from Fanconi disease who have

a congenital deficit in DNA repair are highly susceptible to

these agents which induce acute toxicity with extensive

chromosomal breakage (Berger et al., 1980; Moldovan and

DAndrea, 2009).

In a few standard patients, secondary therapy-induced

AML may occur five to seven years after successful treatment

of the initial malignancy. It then has specific abnormalities

such as 5/5q, 7/7q, 12p. Topoisomerase II-targeteddrugs (ATII), such as etoposide and anthracyclines, may in-

duce the second type of t-AML. It occurs in amedian of 2 years

and is not preceded by MDS. Cytogenetic analysis shows

a high frequency of rearrangements of chromosome band

11q23 but also recurrent balanced rearrangements such as t

(8;21), t(15;17) and inv(16) (Qian et al., 2009).

Secondary tumors can also occur in the absence of treat-

ment but through irradiation accidents. Patients irradiated af-

ter Chernobyl (Tronko et al., 2006) showed a specificity for

radiation-induced rearrangements in thyroid tumors, particu-

larly affecting RET (Nikiforov, 2006).11. Targeted therapies

Chromosomal abnormalities in malignancy have been pivotal

in the discovery of targeted therapy against cancer cells. One

of the first successes came from the discovery that patients

suffering from Fanconi anemia were highly sensitive to

Endoxan, a bifunctional alkylating drug used in the late 70s

for bonemarrow graft conditioning (Berger et al., 1980). A spe-

cific reduced-dose cytotoxic conditioning was proposed for

Fanconi patients allowing successful bone marrow grafts

(Gluckman et al., 1980). That was the first application of ther-

apy following cytogenetic findings.

Retinoic acid in promyelocytic leukemia (PML), initially

proposed in China, induced the maturation of leukemic cells

and the patients achieved a complete remission (Wang and

Chen, 2008). It was rapidly linked to the AML M3 specific t

(15;17) and when the cloning of the breakpoints in PML and

RARA (Retinoic Acid Receptor Alpha) genes was done, a phys-

iopathological mechanism appeared.

The paradigm of CML had become the rule in only ten

years. This malignant proliferation is caused by the consti-

tutively active chimeric tyrosine kinase BCR-ABL. This pro-

tein is encoded by a BCR-ABL fusion gene caused by the t

(9; 22) (q34, q11) translocation designated as the Philadel-

phia chromosome or Ph (Nowell and Hungerford, 1960;

Rowley, 1973).

The Imatinib discovery programwas initiated with the aim

of rationally developing a targeted anticancer approved drug.

A lead compoundwas identified from a screen for inhibitors of

protein kinase C. During the sophisticated optimization of the

molecule structure (Buchdunger et al., 1996; Toledo et al.,

1999), researchers observed that a modification had induced

an inhibitory effect on tyrosine kinases. This property was

then carefully enhanced while PKC inhibition was suppressed

and molecule solubility was increased by other structural ad-

justments in order to allow oral intake. Among the TKs tested,


M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2 319PDGFR and c-KIT were strongly inhibited by this small mole-

cule as well as BCR-ABL in cell lines and animal models. In

1998, the first patient with CML was treated. Imatinib was so

efficient and devoid of major toxicity that the phase III trial

was initiated after only two years and 10 months later the

FDA approved Imatinib for Ph leukemia. As usual, the designprocess took around 8 years, but the clinical development was

remarkably rapid (Druker, 2009; Sherbenou and Druker, 2007).

Thus a second fusion gene, a concept initiated by somatic ge-

neticists from gene mapping, either cytogeneticist or molecu-

lar biologists, has been successfully targeted. The fact that

amajor pharmaceutical laboratorymade such a breakthrough

without losing money on a specific drug for a limited number

of patients opened the way for targeted drugs against proteins

specifically modified by genetic changes in cancer.

Imatinib (Gleevec), induces apoptosis of Ph, BCR-ABLcells in patients, with clinically impressive results: most pa-

tients are in complete cytogenetic remission. Molecular re-

mission can occur but it is not the rule. This remission

seems to persist under permanent treatment. There is some

primary and secondary resistance caused by either overrepre-

sentation of the Ph chromosome, additional chromosomal

rearrangements or mutations at the active site. Those acute

leukemias with the Philadelphia chromosome can also re-

spond to the drug but results are less consistent and relapses

are frequent. A second and even third generation of mole-

cules, Dasatinib, Nilotinib, has been developed that could in-

hibit most resistant ABL mutations and could help to

achieve better patient compliance.

Imatinib is active in other diseases with a constitutionally

active tyrosine kinase. GIST (Gastro-Intestinal Stromal Tumor)

with a KIT mutation respond to it (Duffaud and Le Cesne,

2009). So does an infrequent myeloproliferative disorder, be-

longing to idiopathic hypereosinophilia which is due to a fu-

sion between FIP1L1 and PDGFRA resulting from an

interstitial deletion in 4q12. Imatinib inhibits the chimeric

gene by acting on PDGFRA (Cools et al., 2003). Dermatofibro-

sarcomas protuberans, a slowly growing cutaneous tumor is

characterized by a t(17;22) and a COL1A1-PDGFB fusion gene

whose protein is inhibited by Imatimib (Duffaud and Le

Cesne, 2009).

Other targeted drugs against products of rearranged genes

exist in solid tumors. The epidermal growth factor receptor 2

ERBB2 (HER2), another tyrosine kinase gene, is often amplified

in breast cancer in the formofHSRs (Andre et al., 2009). Among

other tyrosine kinases, Lapatinib can inhibit ERBB2 in breast

cancer. Trastuzamab, a humanized monoclonal antibody

against ERRB2, has demonstrated activity. It is now currently

prescribed to women with a gene amplification because sur-

vival is longer. This amplification is diagnosed by immunohis-

tochemistry and/or ISH (Couturier et al., 2008; Hanna, 2001).

The epidermal growth factor receptor (EGFR) can be either

amplified or mutated in a subset of non-small-cell lung can-

cers (NSCLC) (Dahabreh et al., 2010; Sholl et al., 2009). Gefeti-

nib, Erlotinib are inhibitors of EGFR and approved for use

against those cancers. Cetuximab and Panitunmumab are

monoclonal antibodies against EGFR. The first one has been

approved for the treatment of head and neck cancer and

both are indicated in colon cancer. Many other drugs are un-

der development.12. Role of clinical cytogenomics in the diagnosis,prognosis and in monitoring residual disease

Chromosomal rearrangements are now used clinically as

markers of malignancy.

It is well established that in leukemias and lymphomas,

several rearrangements are highly associatedwith a particular

type of leukemia (Huret, 2010). For example, a t(15;17) is seen

exclusively in acute promyelocytic leukemia, and this anom-

aly has become part of the definition of the entity. That chro-

mosomal abnormalities play a prognostic role is now an

integral part of common practice since most treatment proto-

cols stratify patients according to their karyotype.

The diagnosis of chromosome alterations is required for

the typing and subtyping of sarcomas. The EML-ALK fusion

gene is sought in lung cancer by FISH. The prognosis of neuro-

blastoma is now stratified not only onMYCN amplification but

on segmental rearrangements shown by aCGH. The presence

of segmental copy number aberrations in neuroblastomas

means stratification into a poor prognosis group (Janoueix-

Lerosey et al., 2009). Cerebral tumors are also stratified follow-

ing genomic investigations, like breast tumors, lung cancers

and many other types of cancers.

The diagnosis of residual disease which generally requires

quantification can be assessed using two complementary

methods. The first, quantitative real-time PCR, is a reliable

and sensitive technique, and it yields statistical results. An-

other approach is FISH which is less sensitive, but it provides

a true estimate of malignant cells present. The metaphasic

karyotype has proven clinically very relevant for monitoring

CML. These methods are widely used to detect residual dis-

eased cells in hematology. In solid tumors, the diagnosis of re-

lapses can benefit from genomic knowledge of a primary

tumor in order to design specific probes to show targeted chro-

mosomal rearrangements.13. Databases

Knowledge of cancer genetics is now too massive and is mov-

ing too fast to be fully apprehended by a single individual. For

example, more than 3000 genes are involved in cancer which

is about 14% of the total number of existing genes. It requires

a collective effort facilitated by Web tools that allow interac-

tive consultation. For example, the Atlas of Genetics and Cyto-

genetics in Oncology and Hematology (Huret, 2010), is a free

Internet database that provides summary information and

updates on genes, chromosomal abnormalities, and clinical

entities in onco-hematology. It contains multiple links to the

multiple genomic databases that are expanding like mush-

rooms. Indexed by Current Content, it is considered a scien-

tific journal of international repute and more than 1400

international authors are involved in this work. With thou-

sands of hits per day, it has been top ranked by Google for

the words chromosome cancer.The NCBI/NCI (National Cancer Institute) had created the

Cancer Chromosomes initiative (NCI and NCBI, 2001) which

is based on three databases: the SKY/M-FICH & CGH database,

the NCI Mitelman Database of Chromosome Aberrations in


M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 3 0 9e3 2 2320Cancer which identifies the published cases (Mitelman et al.,

2003), and the NCI Recurrent aberrations in Cancer database.

Each site has its own characteristics and they are more com-

plementary than competitive.

Moreover, the human genome sequence has generated

fantastic tools to investigate the genome of malignant cells.

The identification of genes potentially involved in transloca-

tion, the ability to generate highly specific oligonucleotide

primers, genetic interpretation of array copy number analysis

and whole genome sequencing analysis are among the possi-

bilities now available.14. Prospects

Genomic abnormalities are being increasingly used for the di-

agnosis, prognosis, treatment and tomonitor patients in order

to achieve personalized treatment for cancer. The information

obtained from karyotype studies, high-resolution array CGH,

mitoses and nuclei using FISH and from cells using PCR will

be consistent but each techniquewill contribute its specificity:

karyotype versatility, high-resolution aCGHdetection of unex-

pected events, focused FISH analysis of tumor cells enabling

the differentiation of the proportion of malignant cells and

the very strong sensitivity of PCR. Whole genome sequencing

will be increasingly used in anot toodistant future.Weare cur-

rently experiencing a period of progressive generalization that

is far fromsimple. Tumormaterial is not readily accessible and

possible changes inpracticeswill beneeded.Malignant cell en-

richment is often required. PCR may detect recurrent translo-

cations for the diagnosis but it is currently incapable of

diagnosing additional abnormalities thatmaybe innumerable.15. Conclusion

Acquired chromosomal abnormalities are now considered as

causal inmalignant proliferations. Recurrent chromosomal ab-

normalities, their additive character combined with their mul-

tiplicity in a single tumor are obvious paths in the multi-stage

process of Darwinian oncogenesis. It allows specific chromo-

somal signatures to be identified in more and more tumors

coexisting with possible heterogeneity of the karyotype from

one cell to another, or from a subclone to another. Genomic ab-

normalities are known as the tip of the iceberg because many

small rearrangementsgounnoticedandnewonesaredescribed

each month. Considerable work is still needed in clinical solid

tumor cytogenomics. This approach has proven successful

since it has allowed (and still allows) the identification of a lot

of genes involved in oncogenesis. The black box that remains

the core of a cancer cell is now becoming dark grey. Beyond

progress in concepts and classifications, the designation of tar-

gets for new drugs is creating a new paradigm for cancer ther-

apy. The pharmaceutical industry has proven all its skills in

chemistry, leavinghope for anumerousprogeny to target onco-

genes while finding suitable models for highly specific drugs

with possibly, a more limited market than that observed con-

ventionally. The monotherapy, circumvented by resistance,

will be replaced by a combination of new and old therapies.Acknowledgement

The author thanks Lorna Saint Ange for editing and Bernard

Caillou for helpful discussions.R E F E R E N C E S

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Cytogenomics of cancers: From chromosome to sequenceIntroductionOrigin of chromosomal rearrangements in cancerChromosomal rearrangementsFrom cytogenetics to cytogenomicsIn situ hybridization (ISH)CGHSequenceTypology of genomic abnormalities (chromosome and gene) (Table 3)Evolution of chromosomal abnormalities in tumorsLesions and tumors secondary to physical or chemical mutagensTargeted therapiesRole of clinical cytogenomics in the diagnosis, prognosis and in monitoring residual diseaseDatabasesProspectsConclusionAcknowledgementReferences

cytogenomics of cancers from chromosome to sequence

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