Chromosomal instability (CIN): what it is and why it is ... instability (CIN): what it is and why it is crucial to cancer evolution ... 2 A brief review of CIN research

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<ul><li><p>Chromosomal instability (CIN): what it is and whyit is crucial to cancer evolution</p><p>Henry H. Heng &amp; Steven W. Bremer &amp; Joshua B. Stevens &amp;Steven D. Horne &amp; Guo Liu &amp; Batoul Y. Abdallah &amp;Karen J. Ye &amp; Christine J. Ye</p><p># Springer Science+Business Media New York 2013</p><p>Abstract Results of various cancer genome sequencingprojects have unexpectedly challenged the framework ofthe current somatic gene mutation theory of cancer. Theprevalence of diverse genetic heterogeneity observed incancer questions the strategy of focusing on contributionsof individual gene mutations. Much of the genetic hetero-geneity in tumors is due to chromosomal instability (CIN), apredominant hallmark of cancer. Multiple molecular mech-anisms have been attributed to CIN but unifying these oftenconflicting mechanisms into one general mechanism hasbeen challenging. In this review, we discuss multiple aspectsof CIN including its definitions, methods of measuring, andsome common misconceptions. We then apply the genome-based evolutionary theory to propose a general mechanismfor CIN to unify the diverse molecular causes. In this newevolutionary framework, CIN represents a system behaviorof a stress response with adaptive advantages but also servesas a new potential cause of further destabilization of thegenome. Following a brief review about the newly realizedfunctions of chromosomes that defines system inheritanceand creates new genomes, we discuss the ultimate impor-</p><p>tance of CIN in cancer evolution. Finally, a number ofconfusing issues regarding CIN are explained in light ofthe evolutionary function of CIN.</p><p>Keywords Chromosomal instability (CIN) . Evolutionarymechanism of cancer (EMC) . Genome chaos . Genomeheterogeneity . Genome instability . Genome theory .</p><p>Nonclonal chromosome aberrations (NCCAs) . Systeminheritance</p><p>1 Introduction</p><p>The vast majority of cancers display chromosomal alter-ations [15]. This obvious connection should make chromo-some instability (CIN) a top priority in cancer research.Unfortunately the ultimate importance of chromosomal ab-errations in cancer has been largely ignored in favor ofidentification of cancer genes [6, 7]. Ironically, the shiftfrom identifying cancer-causing chromosome aberrationsto characterizing cancer-causing gene mutations was trig-gered by the successful identification of the Philadelphiachromosome in chronic myelocytic leukemia (CML) andby the subsequent discovery that the BCR-ABL fusion geneis created by this chromosomal translocation [8]. This shiftin focus ushered in the gene cloning era of cancer researchand led to the gene-centric concept that has dominatedresearch for the past four decades.</p><p>Understanding the rationale/history behind such a shift isimportant to re-prioritize CIN research. Prior to the eradominated by gene mutation research, there was a periodwhere chromosomal analyses led the field. At that time itwas hoped that similar to the case of CML, a signaturechromosomal aberration could be identified as the causeof each cancer type. However, most tumors have proven to</p><p>H. H. Heng : S. W. Bremer : J. B. Stevens : S. D. Horne :G. Liu :B. Y. AbdallahCenter for Molecular Medicine and Genetics, Wayne StateUniversity School of Medicine, Detroit, MI, USA</p><p>K. J. YeSeeDNA Inc, Windsor, ON, Canada</p><p>C. J. YeDepartment of Hematology Oncology, Karmanos Cancer Institute,Detroit, MI, USA</p><p>H. H. Heng (*)Department of Pathology, Wayne State University School ofMedicine, Detroit, MI, USAe-mail:</p><p>Cancer Metastasis RevDOI 10.1007/s10555-013-9427-7</p></li><li><p>possess highly heterogeneous patterns of chromosomal ab-errations. Rather than addressing the mechanism and impor-tance of karyotype heterogeneity, research has focused onidentifying defined genetic targets. To many, the real caus-ative factor(s) of cancer must be identifiable as commonlyshared genetic alterations. The ideas of gene mutationsbeing causative factors for cancer and the development ofnew molecular techniques to characterize cancer genes ledto the firm entrenchment of the gene-centric cancer para-digm, which proposes that identification of a handful ofcausal gene mutations will lead to an understanding of themolecular mechanism of cancer and better cancer treatmentsby targeting the mutated gene(s) [911]. Arguments focus-ing on cancer genes rather than chromosomes seem obvious:(1) genes are the basis of genetics and cancer is a geneticdisease so genes must be the causative factors while chro-mosomal aberrations must be the result or by-products ofcancer gene function. (2) Causality of oncogenes has beendemonstrated in model systems and some of these genemutations are detectable in patients, while chromosomalcausality is hard to demonstrate due to the highly diversepatterns that are observed [12]. This has fed the perceptionthat studies characterizing gene mutations or molecularpathways as mechanistic while chromosome based studiesare merely descriptive research.</p><p>The gene concept has failed to deliver. Cancer genomesequencing projects have sequenced thousands of tumorsand demonstrated overwhelmingly that the vast majority ofgenetic changes are not shared among patients [1316]. Thesefindings certainly challenge the current framework of cancertheory [17, 18]. In fact, this outcome was predicted at the verybeginning of the cancer genome sequencing era, as it wasrealized that the current somatic gene mutation theory is basedon a few exceptional cancer types defined by a linear patternof progression such as CML [6, 19]. In contrast, most solidtumors progress stochastically, driven by karyotype alteration-mediated punctuated macroevolution [3, 20].</p><p>Most cancers display overwhelming genetic heterogene-ity [21]. Identification of this heterogeneity, especially at thekaryotype level has resulted in increased attention on CIN.Many independent factors previously thought to causecancer have now been linked to CIN through focus onspecific molecular mechanisms. Few analyses have focusedon karyotypic change as a common mechanism of cancerwithout being linked to any specific gene defined molecularpathway [20, 22, 23]. Even though there has been a dramaticincrease in interest towards CIN, its ultimate importance insomatic evolution has not been fully appreciated [24, 25].This lack of appreciation has led to much confusion in thefield where many me too reports claim to have discov-ered key genes for CIN, although among the increasingnumbers of linkages between genes and CIN, most of theseidentified keys are minor or rare in the patient population</p><p>and have limited clinical implications. In this review, weaddress the following questions: What is CIN? Why is it ofultimate importance in cancer? How should we study it? Inparticular, we reiterate the importance of CIN in thegenome-based evolutionary theory of cancer.</p><p>2 A brief review of CIN research</p><p>The concept of CIN in cancer was first proposed by Boverinearly a century ago [26]. Following the successful identi-fication of the Philadelphia chromosome in 1960, cancercytogeneticists have worked for decades trying to makesense of the diverse karyotype alterations associated with amajority of cancers [27].</p><p>Many early CIN studies focused on chromosome instabilitysyndromes such as Ataxia Telangiectasia, Fanconi Anemia,Bloom Syndrome, and Nijmegen Breakage Syndrome [28].Research has also been directed at the potential link to othercancer types [29] and cancer evolution [30]. The idea of geneticinstability including CIN has also been used to explain themutator phenotype hypothesis [31]. Though there were someestablished molecular mechanisms of genomic instability [32],it was Vogelsteins group who highlighted this issue by classi-fying genetic instability into CIN and micro-satellite instability,reinforcing the idea that most colon cancers are indeed chro-mosomally unstable [33]. Following a series of reports fromVogelsteins group, scattered reports began to suggest that CINwas an important causative factor in most cancers [34]. Forexample, telomere dysfunction was linked to promotingnonreciprocal translocations in epithelial cancers [35],nonhomologous end-joining (NHEJ) was linked to genomicstability and the suppression of chromosome translocations[36], Histone H2AX was linked to suppression of oncogenictranslocations [37], ATM was linked to suppression of aneu-ploidy and subsequent tumor formation [38], germline BUBR1mutations were linked to aneuploidy and cancer predisposition[39], and various new types of chromosomal aberration includ-ing different types of nonclonal chromosome aberrations(NCCAs) were identified and linked to cancer [3]. Together,these exciting reports support the assertion that aneuploidy ismore important than gene mutations in cancer [40, 41].</p><p>As a reflection of the changing attitudes towards chro-mosomal aberrations in cancer, a few popular journals havepublished reviews, opinions, and debates on the importanceof CIN in solid tumors [34, 4244], including experimentaland theoretical evidence on the role CIN plays in the initi-ation of cancer [45], and the possible link between CIN andaneuploidy [46]. The issue of whether NCCAs are importanthas also been raised; as in stark contrast to hematologicalmalignancies, recurrent chromosomal aberrations are rare insolid tumors [2]. It is worth mentioning that an influentialpiece in the Scientific American garnered needed attention</p><p>Cancer Metastasis Rev</p></li><li><p>by pointing out the promise of the chromosome basedcancer theory and the limitations of the popular gene muta-tion theory [47].</p><p>There are two major advances that underscore the impor-tance of CIN. The first is the use of NCCAs to measure CINand the identification and characterization of new types ofchromosomal aberrations that contribute to CIN [3, 20, 48,49]. To date CIN studies have focused primarily on theidentification of clonal chromosome aberrations (CCAs) astraditionally, NCCAs are considered nonsignificant geneticnoise [2, 20, 50]. Analysis of chromosomal aberrations in amodel of cancer evolution led to the realization that seem-ingly random NCCAs actually reflect system instability anddrive cancer evolution by increasing population diversity. Aseries of experiments further demonstrated that CIN (elevat-ed NCCAs) increases multiple times during cancer progres-sion regardless of which causative factor is associatedwith that progression. Therefore, NCCAs best representCIN and CCAs actually represent chromosomal stability[3, 4, 48, 49]. This finding is significant, as it clarifiesconfusion as to which chromosomal aberration types shouldbe used to measure genome stability or instability. Thisadvancement not only links different genetic, epigeneticand environmental factors to CIN, but also demonstratesthat any molecular mechanism can act as a system stressby contributing to the evolutionary mechanism of cancer(EMC; for more, see section below). The EMC unifies thediverse molecular mechanisms of cancer and stochasticgenome aberrations.</p><p>The second major advance stems from the recentcancer genome sequencing projects intended to identifyshared common gene mutations in an unbiased manner[6, 1316]. These studies have revealed extensive mu-tational heterogeneity between tumors. In particular, the-se studies clearly show that the vast majority of cancercases contain complex chromosome alterations. Thoughthese sequencing papers contain limited discussion oncomplex genome rearrangements, their message is sostriking that it has altered popular views of the cancergenome, as many had previously thought that cancercells displayed normal or near-normal karyotypes andthat key gene mutations drove cancer. The prevalence ofthese drastically altered cancer genomes underscores thenew urgency for CIN studies.</p><p>The rapid growth of CIN-related literature documents thegeneral acceptance of CINs importance. Various modelshave been proposed to explain the mechanism of CIN in-cluding: how changing alterations of a specific oncogene ortumor suppressor leads to structural or segmental chromo-somal change [51, 52]; determining the topological featuresof nuclei associated with chromosomal rearrangements [5,53]; determining how replication stress affects genomicintegrity [54]; and explaining the common mechanism of</p><p>aneuploidy [5557]. Obviously, current major efforts stillfocus on individual gene or pathway-based mechanisms asthey link various cancer genes to chromosome re-organization including fusion genes, gene deletions, regula-tory change, and dosage effects.</p><p>Realization of CINs importance raises the question ofwhat is the common mechanism of CIN. In order to link themultitude of diverse molecular mechanisms of CIN, a newframework called the genome theory has been introduced[22, 58]. The genome theory emphasizes the importance ofthe karyotype defining the biological system, how stressleads to adaptation through karyotypic alteration, and howgenome heterogeneity defines the patterns of cancer evolu-tion [7, 20, 5961]. This new synthesis reveals the evolu-tionary meaning of CIN, which not only answers why CINis ultimately more important than other individual molecularmechanisms, but also unifies diverse genetic changes withinan evolutionary framework.</p><p>3 Definition and challenges of measuring CIN</p><p>The definition of CIN seems straightforward. CIN is the rate(cell to cell variability) of changed karyotypes of a given cellpopulation. CIN can be classified as structural CIN or numer-ical CIN [5]. Numerical CIN is determined by gain or loss ofwhole chromosomes or fractions of chromosomes(aneuploidy), while structural CIN is determined by structuralNCCAs. In a normal (nontumorgenic) cell population, CINresults in an increased proportion of cells with aneuploidyand/or structurally altered chromosomes. In a cancer cellpopulation, CIN generates an altered karyotype landscape byincreasing or reducing NCCAs. In practice, however, CIN isdifficult to measure. First, most current high-throughput mo-lecular methods are based on average population profiles andcannot detect cell to cell variability. Therefore to study cell tocell variability tedious molecular cytogenetic analyses arerequired [35, 62, 63]. However, challenges exist in accessingenough mitotic cells in cancer tissues and the identification ofdiverse chromosomal aberration types. Single cell CGH arraysor single cell sequencing can avoid the need of preparingmitotic chromosomes, but a large number of cells are neededto measure CIN, making these impractical on a routine basis.In addition, many chromosomal aberrations are still difficultor impossible to detect without cytogenetic methods. Further-more, to truly measure the rate of chromosomal change,chromosome aberrations must be measured over time in orderto watch evolution in action. This approach is not common inCIN analysis.</p><p>Perhaps the biggest challenge to measuring structural CINis the diversity of chromosomal aberrations. In addition towell-known structural aberrations including simple transloca-tions, complex duplications, deletions, do...</p></li></ul>