cytogenomics of cancers from chromosome to sequence
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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 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: bernheim@igr.fr
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:bernheim@igr.frwww.sciencedirect.comwww.elsevier.com/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
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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 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
Lymphocytic B cell lymphoma, chronic
lymphocytic leukemia
t(14;19)(q32;q13) IGH*BCL3 II
Lymphocytic B cell lymphoma, chronic
lymphocytic leukemia
t(2;14)(p13;q32) BCL11A*IGH II
Lymphocytic B cell lymphoma, chronic
lymphocytic leukemia
del(11)(q23.1) ATM IV
Lymphocytic B cell lymphoma, chronic
lymphocytic leukemia
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
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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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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
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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)
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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 2316
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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 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,
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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 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,
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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 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
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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 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
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