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Review Article

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Chromosome Imbalances in Cancer: Molecular Cytogenetics Meets Genomics

Palumbo E.a, c · Russo A.a, b

Author affiliations

Departments of aBiology and bMolecular Medicine, University of Padova, and c Veneto Institute of Oncology IOV-IRCCS, UOC of Radiotherapy, Padua, Italy

Corresponding Author

Antonella Russo

Department of Molecular Medicine

Via U. Bassi 58/b

IT-35131 Padua (Italy)

E-Mail antonella.russo@unipd.it

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Cytogenet Genome Res 2016;150:176-184

Abstract

Genomic instability is a hallmark of cancer, and it is well-known that in several cancers the karyotype is unstable and rapidly evolving. Molecular cytogenetics has contributed to the description and interpretation of cancer karyotypes, in particular through multicolor FISH approaches which can define even complex chromosome rearrangements. The introduction of genome-wide methods has made available a powerful set of tools with higher resolution than cytogenetics, thus appropriate to comprehend the huge variability of cancer cells. This review focuses on novel findings deriving from the combination of cytogenetic and genomic approaches in cancer research.

© 2017 S. Karger AG, Basel


Chromosomes in Cancer

It is well-known that in several cancers the karyotype is unstable and rapidly evolving [Negrini et al., 2010; Hanahan and Weinberg, 2011]. Furthermore, types and degree of cancer chromosomal imbalances can often provide a diagnostic tool and may be useful to predict the clinical outcome of the tumor [Negrini et al., 2010; Hanahan and Weinberg, 2011; Mitelman et al., 2016]. While some chromosome changes must be considered driver mutations [Mertens et al., 2015], several rearrangements are instead the consequence of the altered cancer cell metabolism (e.g., oxidative stress, defective checkpoints, mutations in DNA repair genes, etc.) which is a cause of genomic instability [Negrini et al., 2010; Hanahan and Weinberg, 2011]. The introduction of molecular cytogenetics has brought about a rapid improvement in the ability to describe and interpret cancer karyotypes, in particular through the multicolor FISH approaches (M-FISH, SKY) developed in the 1990s with the aim to define complex chromosome rearrangements [Schröck et al., 1996; Speicher et al., 1996]. A key innovation was represented by comparative genomic hybridization (CGH), a strategy based on competitive FISH between a reference and a tumor genome, which can unravel chromosome imbalances (but not the presence of balanced rearrangements such as reciprocal translocations or inversions) by a single genome-wide experiment [Kallioniemi et al., 1992]. While the initial approach was strictly based on cytogenetic analysis, a variant introduced a few years later extended the application of CGH to DNA arrays [Solinas-Toldo et al., 1997; Pinkel et al., 1998]. Array-CGH can be considered the first opportunity for cytogenetics to meet genomics: rendering the requirement of conventional (and high-quality) cytogenetic preparations unnecessary (a limiting factor in the case of several solid tumors), array-CGH immediately became a fast and reliable diagnostic tool to define chromosome imbalances in different cancer specimens [Cher et al., 1994; Isola et al., 1994; Lindahl and Willen, 1994; Schröck et al., 1994; Speicher et al., 1994; Suijkerbuijk et al., 1994; Bentz et al., 1995a, b; Iwabuchi et al., 1995; Joos et al., 1995; Kallioniemi et al., 1995; Kim et al., 1995; Levin et al., 1995; Visakorpi et al., 1995; Voorter et al., 1995].

Technical innovation in cytogenetic analyses is still increasing thanks to the development of novel fluorescent probes with improved sensitivity, high-resolution microscopy, and methods to study single cells or single molecules [Speicher and Carter, 2005; Cui et al., 2016]. This is causing revision and refinement of the principles necessary to understand the mechanisms of the origin of chromosome rearrangements in cancer, their eventual causative role, their possible use as biomarkers of cancer evolution or to predict response to therapy [Mertens et al., 2015; Weckselblatt and Rudd, 2015; Willis et al., 2015]. At the same time, the development of genomics made available a powerful set of tools with higher resolution than cytogenetics, thus appropriate to comprehend the huge variability of cancer cells. Early applications aimed at identifying copy number changes in cancer samples, with both diagnostic and discovery goals [Bignell et al., 2004; Weir et al., 2004, 2007; Zhao et al., 2004; Tomlins et al., 2005]. With the introduction of next-generation sequencing and of novel bioinformatic tools suited to interpret the complexity of cancer data sets, a huge amount of information started to be produced. It emerged that mutations and chromosome rearrangements involved in cancer are more frequent and more complex than previously anticipated [Campbell et al., 2008; Stephens et al., 2009; Beroukhim et al., 2010; Bignell et al., 2010]. Deep sequencing of cancer genomes also provided evidence that besides the conventional pathways of double-strand break repair involved in the formation of chromosome rearrangements (i.e., nonhomologous end-joining and homologous recombination [Willis et al., 2015; Kass et al., 2016]), new molecular mechanisms are playing a role.

Remarkably, even highly popular cancer cell lines used worldwide in cancer research remained for a long time only partially characterized at the chromosome and genome level, because apart from the complexity of variations with respect to a normal genome fast divergence is observed among different subclones cultured in diverse laboratories. Multicolor FISH was necessary to obtain a detailed description of the karyotype of different cancer lines, for example the chronic myeloid leukemia K562 cell line [Gribble et al., 2000; Naumann et al., 2001] or HeLa cells [Macville et al., 1999]. However, a complete elucidation of the HeLa genomic landscape was provided only in 2013, more than 60 years after the isolation of this cell line, by means of genomic approaches [Adey et al., 2013; Landry et al., 2013]. A deep understanding of the molecular mechanisms responsible for recurrent translocations was also achieved by the cooperation of cytogenetics and genomics approaches [Rocha and Skok, 2013; Roukos et al., 2013; Mertens et al., 2015].

This review will focus on emerging examples of the efficient application of a combined cytogenetic/genomic approach in cancer research, in particular, (1) the longstanding and still unraveled role of common fragile sites (CFS) in carcinogenesis, and (2) the novel catastrophic mechanisms causing complex chromosome changes discovered in the last 5 years (chromothripsis, kataegis, chromoplexy).

CFS at the Crossroad of Cytogenetics and Genomics

CFS are large genomic regions prone to breakage when human cells are exposed to specific inhibitors of DNA replication [Durkin and Glover, 2007; Sarni and Kerem, 2016]. Most of the known CFS are induced by low concentrations of aphidicolin, but remarkably, the frequency of observed breaks is not uniform among different loci: the most active CFS are FRA3B (3p14.2), FRA6E (6q26), FRA16D (16q23), and FRA7H (7q32.3) [Glover et al., 1984]. Readers interested in the molecular mechanisms behind the instability of CFS may refer to updated reviews [Le Tallec et al., 2014; Ozeri-Galai et al., 2014; Sarni and Kerem, 2016].

CFS have been suggested to be associated with cancer since the pioneering work by Yunis and Soreng [1984] who mapped 51 CFS at the 850-G-band resolution and observed that 20 CFS were located close to recurrent cancer rearrangements known at that time. This observation prompted a burst of studies aiming to understand whether a functional relationship existed between chromosome breakage at CFS and carcinogenesis. CFS were found to be specifically sensitive to mutagens [Yunis et al., 1987], to correspond to preferential sites for integration of viral genomes, both in primary tumors and in cancer cell lines [Popescu and DiPaolo, 1989; Smith et al., 1992; Wilke et al., 1996; Thorland et al., 2000, 2003; Wentzensen et al., 2004], and were suggested to be involved in DNA amplification at oncogenes [Hellman et al., 2002]. In the 1990s, a large number of papers reported the preferential colocalization of CFS, large deletions, and loss of heterozygosity in different cancers, suggesting that CFS could harbor genes with tumor suppressor function [Durkin and Glover, 2007; Lukusa and Fryns, 2008]. In the same years, taking advantage of the growing availability of genomic clones and the development of molecular cytogenetics, the hypothesis was tested for the most active human CFS, leading to the discovery of FHIT at FRA3B [Ohta et al., 1996; Zimonjic et al., 1997; Becker et al., 2002], WWOX at FRA16D [Bednarek et al., 2000; Ludes-Meyers et al., 2003], and PARK2 at FRA6E [Cesari et al., 2003; Denison et al., 2003a] by positional cloning. In the next years, several other studies facilitated the characterization of CFS at the molecular level and the identification of the associated candidate cancer genes [Durkin and Glover, 2007; Lukusa and Fryns, 2008]; remarkably, it turned out that CFS extend over several megabases [Durkin and Glover, 2007; Lukusa and Fryns, 2008], making the positional cloning strategy challenging. The growing availability of genomic databases allowed to define additional features of CFS, which appeared to be enriched not only in cancer genes but also in microRNAs [Calin et al., 2004; Georgakilas et al. 2014] and to be characterized by specific epigenetic changes [Georgakilas et al., 2014]. It was also proved that clusters of interrupted stretches of AT- and TA-dinucleotide repeats, dubbed “flexibility peaks,” can be specifically observed at different CFS [Zlotorynski et al., 2003]. A model of CFS instability was proposed, based on the prediction that sequences at flexibility peaks are prone to form secondary structures [Zlotorynski et al., 2003]. Finally, CFS seem to be enriched in genes of large size [Smith et al., 2006; Le Tallec et al., 2013], but whether this aspect is related to chromosome fragility remains to be fully elucidated.

CFS are cell type-specific [Murano et al., 1989; Le Tallec et al., 2011, 2013; Hosseini et al., 2013], and the response to aphidicolin is characterized by interindividual variability [Tedeschi et al., 1992; Denison et al., 2003b]. This is a critical feature to be considered when evaluating the possible involvement of CFS in carcinogenesis.

Different genome-wide strategies were applied to confirm the implication of CFS in cancer [Bignell et al., 2010; Alexandrov et al., 2013; Barlow et al., 2013; Akagi et al., 2014]. By SNP array, 746 cancer cell lines were genotyped, and the positions of recurrent genome rearrangements were mapped with respect to cancer genes or fragile sites [Bignell et al., 2010]. In agreement with the expectations, several homozygous deletions corresponded to the map position of CFS. Most importantly, in the same study, a specific molecular signature consisting in small (<1 Mb) deletions was defined for fragile sites, which have an intrinsic instability [Bignell et al., 2010]. Noteworthy, this molecular signature was found at a number of positions different from those of known CFS; these positions were classified as “unexplained” deletion clusters [Bignell et al., 2010]. This paper demonstrates the utility of a genome-wide approach to discover new fragility regions which could hardly be detected by conventional cytogenetics, possibly because the frequency of breakage in in vitro conditions is very low.

The fragility of CFS is associated with replication stress, and recent data indicate a role of oncogenes in inducing replication stress [for a review, see Gaillard et al., 2015]. These studies prompted to verify whether oncogene overexpression can trigger chromosome instability in a site-specific manner [Miron et al., 2015]. Interestingly, cancer cells displayed a different (and specific) profile of breaks when different oncogenes were overexpressed and, furthermore, these sites were only partially overlapping with known CFS. At the same time, several oncogene-induced fragile sites colocalized with the positions classified as novel (“unexplained”) fragility regions in the study by Bignell et al. [2010]. Thus, this study, in agreement with the cell type-specific activity of CFS [Murano et al., 1989; Le Tallec et al., 2011, 2013; Hosseini et al., 2013], further confirms that the conventional CFS maps based on aphidicolin exposure cannot be predictive of the cancer response. More importantly, the results provided by Miron et al. [2015] offer a biological explanation for the novel fragility regions described [Bignell et al., 2010], which could represent cancer-specific signatures.

A last example for the potential of genome-wide approaches applied for the analysis of CFS instability in cancer concerns a new group of fragile sequences identified in B lymphocytes [Barlow et al., 2013]. Employing ChIP-seq with proteins detecting single-stranded DNA, sequences were discovered which share different features with CFS: in particular, they colocalize with rearrangements recurrent in lymphomas and, moreover, breaks are formed following replication stress induced by hydroxyurea, ATR inhibition, or deregulated MYC expression [Barlow et al., 2013]. Importantly, according to genome-wide replication analysis (Repli-Seq) [Hansen et al., 2010], these sequences are early replicating, while CFS are well-known late replicating sequences [Durkin and Glover, 2007; Sarni and Kerem, 2016]. In consequence of the above feature, the novel group of fragile sequences is referred to as early replicating fragile sites. Their contribution in cancer demands further investigation.

Chromothripsis (and Other Catastrophes)

According to the classical view, mutations and genetic rearrangements are thought to accumulate stepwise during cancer development [Hanahan and Weinberg, 2011; Vogelstein et al., 2013]. The application of deep sequencing to cancer genomes unraveled however the presence of complex intra- and interchromosome rearrangements involving multiple breakpoints, which cannot be regarded as independent events. A single (or few) chromosome(s) carrying multiple and adjacent intrachromosomal rearrangements is the typical outcome of chromothripsis, a mechanism discovered in 2011 [Stephens et al., 2011]. The observed sequence patterns suggest that deep fragmentation and resealing of the original chromosome(s) have occurred by a unique, catastrophic event. Chromothripsis is indeed a term composed of 2 ancient Greek words, the first one (chromos = stained) is the same used in the definition of chromosomes, while the second one (thripsis = shattering in pieces) is describing the effect detectable at the sequence level. The concept of a single event as the basis of highly complex chromosome rearrangements was novel and contrasted the accepted notion of a progressive accumulation of genetic variations in cancer [Hanahan and Weinberg, 2011; Vogelstein et al., 2013]. Thus, in their original paper, Stephens et al. [2011] considered several aspects to prove that chromothripsis was not an artifactual observation, including a thorough interpretation of the sequence organization of the rearranged chromosome versus the normal genome, FISH validation experiments, and Montecarlo simulations aimed to reinforce the outcome of the bioinformatics analysis.

From this early report [Stephens et al., 2011], a hallmark of chromothripsis appeared to be the presence of deeply rearranged chromosomes carrying several copy number changes which are, however, restricted to few (possibly 2) copy number states. Loss of heterozygosity must be present in one of the oscillating states. Additional criteria for distinguishing chromothripsis from other mechanisms causing complex chromosome changes were then defined [Korbel and Campbell, 2013]. For example, orientation and position of the rearranged segments are important to differentiate chromothripsis from a mechanism of breakage-fusion-breakage. In the former, DNA segments must be rearranged randomly, while in the latter, a prevalence of tail-to-tail or head-to-head junctions is expected. This means that data obtained by microarray analyses [Kim et al., 2013; Przybytkowski et al., 2014] are not fully informative, and also exome sequencing [Kim et al., 2015] is limited with respect to massive DNA sequencing [Campbell et al., 2008]. Breakpoint junction sequencing indicates another feature of the molecular signature of chromothripsis, i.e., the presence of imperfect junctions typical of repair by nonhomologous end-joining and the lack of replication-based homology [Korbel and Campbell, 2013; Willis et al., 2015]. Initially strongly debated [Righolt and Mai, 2012; Kinsella et al., 2014], the relevance of chromothripsis in cancer has grown in a few years as several tumors were investigated, and the issue of tumor heterogeneity, which could represent a confounding factor, was considered [Kloosterman et al., 2011; Nik-Zainal et al., 2012; Rausch et al., 2012; Kim et al., 2013, 2015; MacKinnon and Campbell, 2013; Malhotra et al., 2013; Zack et al., 2013; Kloosterman et al., 2014; Nones et al., 2014]. Finally, experimental evidence based on single-cell live imaging and genomics was provided in support of the occurrence of chromothripsis [Kloosterman, 2015; Zhang et al., 2015].

How frequent is chromothripsis in cancer? This question remains unanswered as the database is still scanty; moreover, up to now data were accumulated under rather heterogeneous criteria, as it is reasonable when novel phenomena start to be understood. The range is certainly wide, in the order of 2-40%, and the possibility exists that in some tumor types chromothripsis occurs with high probability [Zack et al., 2013; Kloosterman et al., 2014; Rode et al., 2016].

While it is obvious that chromothripsis may have powerful consequences for cell transformation, as it produces extensive genomic alterations in a single step, the molecular mechanism(s) behind the event remain(s) elusive. Indeed, not only the formation of a huge number of double-strand breaks must be postulated to have occurred simultaneously in the cell, but at the same time, it must be explained how and why this is restricted to single (or few) chromosomes (one major hallmark of chromothripsis [Korbel and Campbell, 2013]). An intriguing possibility for a single chromosome to undergo deep shattering followed by random reassembly is related to the existence of micronuclei, cytoplasmic structures than can derive from chromosome lagging at the mitotic division [Fenech et al., 2011]. Micronuclei can undergo DNA pulverization, and reincorporation of their content in the main nucleus can occur [Crasta et al., 2012]. Since micronuclei represent a transient condition of isolation of a single (or few) chromosome(s) at interphase, the idea that chromothripsis may follow shattering and random reassembly of the chromosome(s) harbored within a micronucleus has been put forward [Crasta et al., 2012]. Recently, the hypothesis proved to be correct by an elegant experiment combining live-cell imaging and single-cell sequencing [Zhang et al., 2015].

According to the molecular patterns detected in different cases of chromothripsis, additional mechanisms can act before or after the catastrophic event leading to the final picture detected by deep sequencing of cancer specimens. For example, several studies indicate that telomere erosion may be involved in chromothripsis. This contribution must not be confused with the well-known mechanism by which telomere shortening triggers the breakage-fusion-bridge (BFB) process, originally discovered by Barbara McClintock [McClintock, 1941]. BFB can indeed produce complex rearrangements including those involved in carcinogenesis, but this outcome implies the occurrence of multiple events of chromosome breakages [Hanahan and Weinberg, 2011; Willis et al., 2015]. Recently, telomere dysfunction has been associated with the occurrence of chromothripsis in cell culture [Maciejowski et al., 2015; Mardin et al., 2015]. A different study investigating telomere length and telomere stability reported that telomere size correlates with presence/absence of chromothripsis in several tumor samples, and it proposed that telomere stabilization can follow chromothripsis, in order to preclude additional catastrophic events for the tumor [Ernst et al., 2016]. These findings only indirectly suggest a mechanism connecting telomere dysfunction and chromothripsis, but the issue deserves attention.

Regarding the immediate consequences of chromothripsis, double minutes, a well-known feature of cancer cells [Mitelman et al., 2016], have been proposed to represent a possible product [Stephens et al., 2011; Rausch et al., 2012]. This intriguing link, however, was not confirmed by a study carried out with cancer cell lines [L'Abbate et al., 2014]. The possibility of an association between chromothripsis and ring chromosomes (which can play a role in several cancer forms) has also been suggested in a study evaluating different liposarcomas [Garsed et al., 2014]. According to the molecular profiles, chromosome 12 appeared to be involved in chromothripsis originating a ring chromosome. Interestingly, to explain the observed sequence organization, it must be assumed that the initiating event was followed by several additional chromosome changes including BFB, centromere loss, and neocentromere formation. This study underpins the necessity to interpret the genomic profiles with special attention for the temporal events causing the final chromosome rearrangements, because a complex interplay of diverse molecular mechanisms may be involved [Garsed et al., 2014].

However, the final major consequences of chromothripsis appear to be the loss of tumor suppressor genes, gene fusion, and gene dysregulation [Zack et al., 2013], all of them typical features of cancer, although produced by a unique and catastrophic event instead of gradual accumulation of genetic changes. Readers interested in chromothripsis will find an updated discussion of the possible molecular mechanisms and the role in developmental pathologies other than cancer in recent reviews [Leibowitz et al., 2015; Storchová and Kloosterman, 2016].

Traces of additional types of catastrophic events have been recorded in cancer genomes in the recent years: kataegis (a Greek word meaning thunderstorm) is the definition of a cluster of point mutations near chromosome breakpoints [Alexandrov et al., 2013]. The phenomenon was originally described in a study of breast cancer specimens [Nik-Zainal et al., 2012]. By sequence profiling, it emerged that APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) cytidine deaminases, a class of enzymes acting in DNA repair [Chan and Gordenin, 2015; Swanton et al., 2015], could be involved in kataegis. Not only the nature of point mutations (C-to-T transitions and C-to-G transversions), but also their clustered location and the strand coordination observed (meaning that a same type of nucleotide change is found in the same strand) were in agreement with the molecular process mediated by APOBEC [Chan and Gordenin, 2015; Swanton et al., 2015]. Further experiments in yeast confirmed that kataegis is driven by the occurrence of double-strand breaks and the activity of APOBEC enzymes [Taylor et al., 2013], thus reinforcing the nonrandom association of hypermutated sites and chromosome breakpoints observed in breast cancer [Nik-Zainal et al., 2012]. When deregulated, APOBEC enzymes may be responsible for hypermutator phenotypes, and they are also considered driving forces for tumor subclonal heterogeneity [Chan and Gordenin, 2015; Swanton et al., 2015].

Kataegis is therefore an interesting mechanism in cancer biology, in which one event of chromosome breakage can be the cause of a hypermutation effect.

Chromoplexy has been originally described in prostate cancer where several unclustered chained rearrangements involving 2 or more chromosomes were found by whole-genome sequencing [Baca et al., 2013]. The term is indeed derived from the ancient Greek word plexus that means braiding. The analysis demonstrated that the frequency of the rearrangements can be impressive and involving the large majority of samples. Interpretation of sequence data indicated that the diverse rearrangements were formed simultaneously causing gene fusion, including TMPRSS2-ERG, a hallmark of prostate cancer [Tomlins et al., 2005], and large deletions [Baca et al., 2013]. Concerning its origin, chromoplexy seems to be related to a transcriptional mechanism when coexpressed loci are involved. This can explain the final result, which is an accumulation of linked translocations.

With respect to cancer evolution, an interesting difference between chromothripsis and chromoplexy is that the former is considered an early event [Leibowitz et al., 2015; Storchová and Kloosterman, 2016], while the latter can occur repeatedly and at different times of prostate cancer evolution [Baca et al., 2013]. This can contribute to increased intratumor heterogeneity and subcloning.

To understand the relevance of catastrophic events and to evaluate their contribution to cancer evolution, novel bioinformatics tools have been developed, and criteria of analysis were established [Korbel and Campbell, 2013; Govind et al., 2014; Moncunill et al., 2014; Yang et al., 2016a, b]. But after genomics has paved the way for the discovery of novel types of complex chromosomal rearrangements, in turn the cytogenetic expertise is necessary to validate the models and gain full comprehension of the mechanisms leading to chromothripsis and other catastrophes [MacKinnon and Campbell, 2013]. For example, Li et al. [2014] carried out an interdisciplinary effort to decipher the origin and the evolution of cancer rearrangements. They evaluated the case of iAMP21-ALL, which is a form of acute lymphoblastic leukemia (ALL) associated with the amplification of a genomic region from chromosome 21 and representing a separate subgroup in this disease [Moorman et al., 2007]. In patients with iAMP21-ALL, FISH analyses and copy number profiling led to define a model in which a primary event, BFB, generated the amplification of chromosome 21, while chromothripis fixed it, and cancer is generated by a final chromosome duplication. In the above study, authors found that children carrying a robertsonian translocation involving chromosomes 15 and 21 have a 2,700-fold higher risk to develop iAMP21-ALL; this was interpreted because of the propensity of the robertsonian chromosome to undergo anaphase defects and BFB due to its dicentric organization [Li et al., 2014]. This paper is therefore a good example of the importance to carry out synergistic analyses to elucidate the complex pathways which may lead from genome instability to cancer development [Russo et al., 2015].

Concluding Remarks

A thorough knowledge of the cancer genome is fundamental for achieving several goals in cancer research: fast and precise diagnosis, therapeutic strategies, recurrence risk estimation, and survival prediction.

Here, we discussed recent advances concerning the assessment of chromosome rearrangements in cancer by genome-wide approaches. While, in this review, we focused the attention on structural rearrangements in cancer, it must be emphasized that the large majority of tumors have an aneuploid chromosome set [Thompson and Compton, 2011; McGranahan et al., 2012; Tanaka and Hirota, 2016]. Molecular mechanisms of cancer rearrangements are described in recent and complete reviews [Mertens et al., 2015; Weckselblatt and Rudd, 2015; Willis et al., 2015].

Do we still need a cytogenetic approach in the next-generation sequencing era? The answer is yes: cytogenetics and genomics may complement each other successfully in cancer research. Although genomics offers the possibility to describe subtle variations that are under the microscope resolution, cytogenetics maintains the possibility to describe the state of a single cell, and therefore to focus on mosaicism and tumor heterogeneity. In addition, cytogenetics remains the fundamental tool for validation of genomics results.

Acknowledgements

Literature contributing to cancer genetics and cytogenetics is wide; we regret that we were not able to cite all of the papers that have contributed to the topics discussed in this review. E.P. and A.R. are supported by the University of Padova (PRAT2014 CPDA142715) and by IOV-IRCCS.

Disclosure Statement

The authors have no conflicts of interest to declare.


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Author Contacts

Antonella Russo

Department of Molecular Medicine

Via U. Bassi 58/b

IT-35131 Padua (Italy)

E-Mail antonella.russo@unipd.it


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