23713010	Review and Opinion			Department of Medicine; Institute for Stem Cell and Regenerative Medicine; University of Washington School of Medicine; Seattle, WA USA	Maxwel M. Krem1, Marshall S. Horwitz	Mitotic errors, aneuploidy and micronuclei in Hodgkin lymphoma pathogenesis	Commun Integr Biol	2013 May	The Reed-Sternberg (RS) cell is the driving force behind Hodgkin lymphoma (HL), a unique malignancy in which the rare RS cell creates an inflammatory microenvironment that recruits a reactive tumor infiltrate. Well-known oncogenic factors such as nuclear factor kappa B (NFkappaB) signaling and Epstein-Barr virus infection are linked to HL pathogenesis but do not adequately explain the RS cell's key pathologic features of multi-nucleation, abnormalities of centrosome function and number and aneuploidy. Chromosomal instability is also considered a key pathway in the origin of the RS cell, though the molecular mechanisms have largely been a black box. We demonstrated that the midbody kelch domain protein KLHDC8B protects against mitotic errors, centrosomal amplification and chromosomal instability. Here we discuss how the new findings linking KLHDC8B to mitoticintegrity and faithful chromosomal segregation are providing mechanistic explanations for the origin of the RS cell and the molecular pathogenesis of chromosomal instability in HL.	Homo sapiens				NA	NA	NA
24282781	Review and Opinion			Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA	German A. Pihan	Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer	Front Oncol	2013 Nov	The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.					NA	NA	NA
24305569	Review and Opinion	Colorectal cancer		Department of Medical Genetics, University Medical Center Utrecht, Utrecht and bDepartment of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands	Wigard P. Kloosterman, Jan Koster, and Jan J. Molenaar	Prevalence and clinical implications of chromothripsis in cancer genomes	Curr Opin Oncol	2014 Jan	PURPOSE OF REVIEW: A variety of mutational mechanisms shape the landscape of somatic mutations in cancer genomes. Although the contribution of single nucleotide mutations is well studied, getting a hold of structural genomic rearrangements is more difficult due to their complexity and diversity in sizes and classes. Here, we discuss the incidence of complex genomic rearrangements and their impact on cancer development and progression. RECENT FINDINGS: Catastrophic genome rearrangements have recently been described in various cancer genomes. Such complex genomic rearrangements may be a result of local shattering of chromosomes followed by reassembly of DNA fragments, a process termed chromothripsis. In addition, DNA replication errors may lead to complex genomic rearrangements in cancer. Complex reshuffling of chromosomes can cause formation of gene fusions, disruption of tumor suppressors, and amplification of oncogenes. Furthermore, the occurrence of chromothripsis has been associated with poor prognosis in neuroblastoma, melanoma, and multiple myeloma. SUMMARY: Complex genomic rearrangements, such as chromothripsis, may affect cancer gene function and thereby have a major impact on cancer progression, prognosis, and therapy response.					NA	NA	NA
24187453	Review and Opinion			MRC Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea	Tae-Min Kim, Sug-Hyung Lee, Yeun-Jun Chung	Clinical applications of next-generation sequencing in colorectal cancers	World J Gastroenterol	2013 Oct	Like other solid tumors, colorectal cancer (CRC) is a genomic disorder in which various types of genomic alterations, such as point mutations, genomic rearrangements, gene fusions, or chromosomal copy number alterations, can contribute to the initiation and progression of the disease. The advent of a new DNA sequencing technology known as next-generation sequencing (NGS) has revolutionized the speed and throughput of cataloguing such cancer-related genomic alterations. Now the challenge is how to exploit this advanced technology to better understand the underlying molecular mechanism of colorectal carcinogenesis and to identify clinically relevant genetic biomarkers for diagnosis and personalized therapeutics. In this review, we will introduce NGS-based cancer genomics studies focusing on those of CRC, including a recent large-scale report from the Cancer Genome Atlas. We will mainly discuss how NGS-based exome-, whole genome- and methylome-sequencing have extended our understanding of colorectal carcinogenesis. We will also introduce the unique genomic features of CRC discovered by NGS technologies, such as the relationship with bacterial pathogens and the massive genomic rearrangements of chromothripsis. Finally, we will discuss the necessary steps prior to development of a clinical application of NGS-related findings for the advanced management of patients with CRC.					NA	NA	NA
24298051	Review and Opinion			Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA	Cheng-Zhong Zhang, Mitchell L. Leibowitz, David Pellman	Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements	Genes Dev	2013 Dec	Recent genome sequencing studies have identified several classes of complex genomic rearrangements that appear to be derived from a single catastrophic event. These discoveries identify ways that genomes can be altered in single large jumps rather than by many incremental steps. Here we compare and contrast these phenomena and examine the evidence that they arise "all at once." We consider the impact of massive chromosomal change for the development of diseases such as cancer and for evolution more generally. Finally, we summarize current models for underlying mechanisms and discuss strategies for testing these models.					NA	NA	NA
23730541	Review and Opinion			Departments of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, New Research Building, Room 160D, 77 Avenue Louis Pasteur, Boston, MA 02115, USA	Benjamin B. Currall, Colby Chiangmai, Michael E. Talkowski, Cynthia C. Morton	Mechanisms for Structural Variation in the Human Genome	Curr Genet Med Rep	2013 Jun	It has been known for several decades that genetic variation involving changes to chromosomal structure (i.e., structural variants) can contribute to disease; however this relationship has been brought into acute focus in recent years largely based on innovative new genomics approaches and technology. Structural variants (SVs) arise from improperly repaired DNA double-strand breaks (DSB). DSBs are a frequent occurrence in all cells and two major pathways are involved in their repair: homologous recombination and non-homologous end joining. Errors during these repair mechanismscan result in SVs that involve losses, gains and rearrangements ranging from a few nucleotides to entire chromosomal arms. Factors such as rearrangements, hotspots and induced DSBs are implicated in the formation of SVs. While de novo SVs are often associated with disease, some SVs are conserved within human subpopulations and may have had a meaningful influence on primate evolution. As the ability to sequence the wholehuman genome rapidly evolves, the diversity of SVs is illuminated, including very complex rearrangements involving multiple DSBs in a process recently designated as chromothripsis. Elucidating mechanisms involved in the etiology of SVs informs disease pathogenesis as well as the dynamic function associated with the biology and evolution of human genomes.					NA	NA	NA
24452388	Review and Opinion			Departments of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, New Research Building, Room 160D, 77 Avenue Louis Pasteur, Boston, MA 02115, USA	Franck Pellestor	Chromothripsis: how does such a catastrophic event impact human reproduction 	Hum Reprod	2014 Jan	The recent discovery of a new kind of massive chromosomal rearrangement, baptized chromothripsis (chromo for chromosomes, thripsis for shattering into pieces), greatly modifies our understanding of molecular mechanisms implicated in the repair of DNA damage and the genesis of complex chromosomal rearrangements. Initially described in cancers, and then in constitutional rearrangements, chromothripsis is characterized by the shattering of one (or a few) chromosome(s) segments followed by a chaotic reassembly of the chromosomal fragments, occurring during one unique cellular event. The diversity and the high complexity of chromothripsis events raise questions about their origin, their ties to chromosome instability and their impact in pathology. Several causative mechanisms, involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation and p53 inactivation, have been proposed. The remarkable point is that all these mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and chromosomal abnormalities. Consequently, it seems important to consider this unexpected catastrophicphenomenon in the context of fertilization and early embryonic development in order to discuss its potential impact on human reproduction.	Homo sapiens				NA	NA	NA
23804754	Review and Opinion			Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany	Agnes Schipler, George Iliakis	DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice	Nucleic Acids Res	2013 Jun	Although the DNA double-strand break (DSB) is defined as a rupture in the double-stranded DNA molecule that can occur without chemical modification in any of the constituent building blocks, it is recognized that this form is restricted to enzyme-induced DSBs. DSBs generated by physical or chemical agents can include at the break site a spectrum of base alterations (lesions). The nature and number of such chemical alterations define the complexity of the DSB and are considered putative determinants for repair pathway choice and the probability that errors will occur during this processing. As the pathways engaged in DSB processing show distinct and frequently inherent propensities for errors, pathway choice also defines the error-levels cells opt to accept. Here, we present a classification of DSBs on the basis of increasing complexity and discuss how complexity may affect processing, as well as how it may cause lethal or carcinogenic processing errors. By critically analyzing the characteristics of DSB repair pathways, we suggest that all repair pathways can in principle remove lesions clustering at the DSB but are likely to fail when they encounter clusters of DSBs that cause a local form of chromothripsis. In the same framework, we also analyze the rational of DSB repair pathway choice.					NA	NA	NA
23744564	Review and Opinion			Vancouver Prostate Center and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.	Wyatt AW, Collins CC	In Brief: Chromothripsis and cancer	J Pathol	2013 Sep	Chromothripsis is a one-step catastrophic event which plays an important role during cancer development. During chromothripsis, tens to hundreds of genomic rearrangements can occur within localized regions of the genome, and lead to the simultaneous creation of multiple cancer-driving aberrations. Given that chromothripsis has a cancer-wide incidence of 2-3%, its recent discovery has significant implications for our understanding of tumour biology and evolution.					NA	NA	NA
22440479	Review and Opinion			Department of Molecular andHumanGenetics, Baylor College of Medicine, Houston, TX 77030, USA	Pengfei Liu, Claudia MB Carvalho, PJ Hastings, James R Lupski	Mechanisms for recurrent and complex human genomic rearrangements	Curr Opin Genet Dev	2012 Jun	During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed.					NA	NA	NA
23327985	Review and Opinion			Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Knight Cancer Institute, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA	Nathan Donley, Mathew J. Thayer	DNA replication timing, genome stability and cancer Late and/or delayed DNA replication timing is associated with increased genomic instability	Semin Cancer Biol	2013 Apr	Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of chromothripsis and kataegis. In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.					NA	NA	NA
25439810	Review and Opinion			Laboratory of Chromosomal Genetics, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier CHRU	Pellestor F, Gatinois V, Puechberty J, Genevieve D, Lefort G.	Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review	Fertil Steril	2014 Dec	OBJECTIVE: To review the discovery of chromothripsis and analyze its impact on human reproduction. DESIGN: Database and literature analysis. SETTING: University hospital. PATIENT(S): Carriers of massive and complex chromosomal rearrangements. INTERVENTION(S): Cytogenetic analysis and molecular testing (fluorescence in situ hybridization, microarray, whole-genome sequencing). MAIN OUTCOME MEASURE(S): Chromothripsis occurrence in human gametes and preimplantation embryos, with regard to the potential causative mechanisms described in literature. RESULT(S): Databases were searched for the literature published up to March 2014. Chromothripsis is characterized by the shattering of one (or a few) chromosome segments followed by a haphazard reassembly of the fragments generated, arising through a single initial catastrophic event. Several mechanisms involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation, and p53 inactivation might cause chromothripsis. The remarkable point is that all these plausible mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and the genesis of chromosomal abnormalities. Specific features of gametogenesis and early embryonic development such as the weakness of cell cycle and mitosis checkpoints and the rapid kinetics of division in germ cells and early cleavage embryos may contribute to the emergence of chromothripsis. CONCLUSION(S): The discovery of this new class of massive chromosomal rearrangement has deeply modified our understanding on the genesis of complex genomic rearrangements. Data presented in this review support the assumption that chromothripsis could operate in human germlines and during early embryonic development. Chromothripsis might arise more frequently than previously thought in both gametogenesis and early human embryogenesis.					NA	NA	NA
25989073	Review and Opinion	Pediatric cancer		Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.	Hatch EM, Hetzer MW.	Chromothripsis	Curr Biol	2015 May	Hatch and Hetzer provide an introduction to chromothripsis - 'chromosome shattering' - and its involvement in cancer.					NA	NA	NA
25982339	Review and Opinion	Acute lymphoblastic leukemia		Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany	Kuhlen M, Borkhardt A	Cancer susceptibility syndromes in children in the area of broad clinical use of massive parallel sequencing.	Eur J Pediatr	2015 May	Children diagnosed with cancer are considered for inherited cancer susceptibility testing according to well-established clinical criteria. With increasing efforts to personalize cancer medicine, comprehensive genome analyses will find its way into daily clinical routine in pediatric oncology. Whole genome and exome sequencing unavoidably generates incidental findings. The somatic molecular make-up of a tumor genome may suggest a germline mutation in a cancer susceptibility syndrome. At least two mechanisms are well-known, (a) chromothripsis (Li-Fraumeni syndrome) and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type (defective DNA mismatch repair). Hence, pediatricians are faced with the fact that genetic events within the tumor genome itself can point toward underlying germline cancer susceptibility. Whenever genetic testing including next-generation sequencing (NGS) is initiated, the pediatrician has to inform about the benefits, risks, and alternatives, discuss the possibility of incidental findings and its disclosure, and to obtain informed consent prior to testing. CONCLUSIONS: Genetic testing and translational research in pediatric oncology can incidentally uncover an underlying cancer susceptibility syndrome with implications for the entire family. Pediatricians should therefore increase their awareness of chances and risks that accompany the increasingly wide clinical implementation of NGS platforms. What is Known: The proportion of cancers in children attributable to an underlying genetic syndrome or inherited susceptibility is unclear. Pediatricians consider children diagnosed with cancer for inherited cancer susceptibility according to well-established clinical criteria. What is New: Genetic testing of tumor samples can incidentally uncover an underlying cancer susceptibility syndrome. Findings in tumor genetics can be indicative that the tumor arose on the basis of the child's germline alteration, (a) chromothripsis and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type.					NA	NA	NA
26091034	Review and Opinion			Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies 10010 North Torrey Pines Road, La Jolla, 92037 CA, USA	Hatch EM, Hetzer MW	Linking Micronuclei to Chromosome Fragmentation.	Cell	2015 Jun	Human cancer cells bear complex chromosome rearrangements that can be potential drivers of cancer development. However, the molecular mechanisms underlying these rearrangements have been unclear. Zhang et al. use a new technique combining live-cell imaging and single-cell sequencing to demonstrate that chromosomes mis-segregated to micronuclei frequently undergo chromothripsis-like rearrangements in the subsequent cell cycle.					NA	NA	NA
26084493	Review and Opinion				Waldron D	Genome stability: Chromothripsis and micronucleus formation.	Nat Rev Genet	2015 Jun	It has generally been assumed that cancers arise through the accumulation of individual muta- tions over time; however, recent cancer genome sequence analyses suggest that multiple mutations can arise simultaneously during a single event such as chromothripsis, which results in extensive genomic rearrangements that are usually con- fined to a single chromosome. 					NA	NA	NA
21215363	Review and Opinion			Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115	Matthew Meyerson, David Pellman	Cancer Genomes Evolve by Pulverizing Single Chromosomes	Cell	2011 Jan	A report in this issue describes chromothripsis a new mechanism for genetic instability in cancer cells. Chromothripsis appears to be a cataclysmic event in which a single chromosome is fragmented and then reassembled. The phenomenon raises important questions of how chromosome rearrangements can be confined to defined genome segments.					NA	NA	NA
22265399	Review and Opinion			The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA	Maher CA, Wilson RK	Chromothripsis and Human Disease: Piecing Together the Shattering Process	Cell	2012 Jan	The unprecedented resolution of high-throughput genomics has enabled the recent discovery of a phenomenon by which specific regions of the genome are shattered and then stitched together via a single devastating event, referred to as chromothripsis. Potential mechanisms governing this process are now emerging, with implications for our understanding of the role of genomic rearrangements in development and disease.					NA	NA	NA
23153487	Review and Opinion			Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA	Jones MJ, Jallepalli PV	Chromothripsis: Chromosomes in Crisis	Cell	2012 Nov	During oncogenesis, cells acquire multiple genetic alterations that confer essential tumor-specific traits, including immortalization, escape from antimitogenic signaling, neovascularization, invasiveness, and metastatic potential. In most instances, these alterations are thought to arise incrementally over years, if not decades. However, recent progress in sequencing cancer genomes has begun to challenge this paradigm, because a radically different phenomenon, termed chromothripsis, has been suggested to cause complex intra- and interchromosomal rearrangements on short timescales. In this Review, we review established pathways crucial for genome integrity and discuss how their dysfunction could precipitate widespread chromosome breakage and rearrangement in the course of malignancy.					NA	NA	NA
22901976	Review and Opinion			Cancer Biology and Pharmacology, Genome Institute of Singapore, 60 Biopolis Street, Genome, Singapore 138672, Singapore	Inaki K, Liu ET	Structural mutations in cancer: mechanistic and functional insights	Trends Genet	2012 Nov	Next-generation sequencing (NGS) has enabled the comprehensive and precise identification of many somatic structural mutations in cancer. Analyses integrating point mutation information with data on rearrangements and copy number variation have revealed a higher-order organization of the seemingly random genetic events that lead to cancer. These meta-analyses provide a more refined view of the mutational mechanisms, genomic evolution, and combinations of mutations that contribute to tumorigenesis. Structural mutations, or genome-scale rearrangements of segments of DNA, may play a hitherto unappreciated role in cancer through their ability to move blocks of adjacent genes simultaneously, leading to concurrent oncogenic events. Moreover, whole-genome sequencing (WGS) data from tumors have revealed global rearrangements, such as those seen in the tandem duplicator phenotype and in chromothripsis, suggesting that massive rearrangements are a specific cancer phenotype. Taken together, the emerging data suggest that the chromosome structure itself functions as a systems oncogenic organizer.					NA	NA	NA
23266571	Review and Opinion			Lab of Bioinformatics and Systems Biology, National Research Council Canada, Montreal, Canada; McGill University Center for Bioinformatics, Montreal, Canada.	Edwin Wang	Understanding genomic alterations in cancer genomes using an integrative network approach	Cancer Lett	2013 Nov	In recent years, cancer genome sequencing and other high-throughput studies of cancer genomes have generated many notable discoveries. In this review, novel genomic alteration mechanisms, such as chromothripsis (chromosomal crisis) and kataegis (mutation storms), and their implications for cancer are discussed. Genomic alterations spur cancer genome evolution. Thus, the relationship between cancer clonal evolution and cancer stems cells is commented. The key question in cancer biology concerns how these genomic alterations support cancer development and metastasis in the context of biological functioning. Thus far, efforts such as pathway analysis have improved the understanding of the functional contributions of genetic mutations and DNA copy number variations to cancer development, progression and metastasis. However, the known pathways correspond to a small fraction, plausibly 5-10%, of somatic mutations and genes with an altered copy number. To develop a comprehensive understanding of the function of these genomic alterations in cancer, an integrative network framework is proposed and discussed. Finally, the challenges and the directions of studying cancer omic data using an integrative network approach are commented.					NA	NA	NA
23478216	Review and Opinion			Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands	Kloosterman WP, Cuppen E	Chromothripsis in congenital disorders and cancer: similarities and differences	Curr Opin Cell Biol	2013 Jun	Genomic rearrangements may give rise to congenital disease and contribute to cancer development. Recent evidence has shown that very complex genomic rearrangements in cancer cells can result from a single catastrophic event of massive DNA breakage and repair, termed chromothripsis. This results in heavily rearranged chromosomes comprising frequent sequence losses. A very similar process of chromosome shattering is found for complex chromosome rearrangements in the germline of patients with congenital disorders. Here, we review the literature on chromothripsis in cancer and congenital disease. We describe differences and similarities for chromothripsis rearrangements in somatic tissue and the germ line and we discuss the cellular origin and molecular mechanisms of chromothripsis.					NA	NA	NA
21802523	Review and Opinion			Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom	Colnaghi R, Carpenter G, Volker M, O'Driscoll M	The consequences of structural genomic alterations in humans: Genomic Disorders, genomic instability and cancer	Semin Cell Dev Biol	2011 Oct	Over the last decade or so, sophisticated technological advances in array-based genomics have firmly established the contribution of structural alterations in the human genome to a variety of complex developmental disorders, and also to diseases such as cancer. In fact, multiple 'novel' disorders have been identified as a direct consequence of these advances. Our understanding of the molecular events leading to the generation of these structural alterations is also expanding. Many of the models proposed to explain these complex rearrangements involve DNA breakage and the coordinated action of DNA replication, repair and recombination machinery. Here, and within the context of Genomic Disorders, we will briefly overview the principal models currently invoked to explain these chromosomal rearrangements, including Non-Allelic Homologous Recombination (NAHR), Fork Stalling Template Switching (FoSTeS), Microhomology Mediated Break-Induced Repair (MMBIR) and Breakage-fusion-bridge cycle (BFB). We will also discuss an unanticipated consequence of certain copy number variations (CNVs) whereby the CNVs potentially compromise fundamental processes controlling genomic stability including DNA replication and the DNA damage response. We will illustrate these using specific examples including Genomic Disorders (DiGeorge/Veleocardiofacial syndrome, HSA21 segmental aneuploidy and rec (3) syndrome) and cell-based model systems. Finally, we will review some of the recent exciting developments surrounding specific CNVs and their contribution to cancer development as well as the latest model for cancer genome rearrangement; 'chromothripsis'.					NA	NA	NA
22100908	Review and Opinion	Prostate cancer		Institut National de la Sante et de la Recherche Medicale (INSERM), U613, Brest, France	Chen JM, Ferec C, Cooper DN	Transient hypermutability, chromothripsis and replication-based mechanisms in the generation of concurrent clustered mutations	Mutat Res	2011 Nov	Clustered mutations may be broadly defined as the presence of two or more mutations within a spatially localized genomic region on a single chromosome. Known instances vary in terms of both the number and type of the component mutations, ranging from two closely spaced point mutations to tens or even hundreds of genomic rearrangements. Although clustered mutations can represent the observable net result of independent lesions sequentially acquired over multiple cell cycles, they can also be generated in a simultaneous or quasi-simultaneous manner within a single cell cycle. This review focuses on those mechanisms known to underlie the latter type. Both gene conversion and transient hypermutability are capable of generating closely spaced multiple mutations. However, a recently described phenomenon in human cancer cells, known as 'chromothripsis', has provided convincing evidence that tens to hundreds of genomic rearrangements can sometimes be generated simultaneously via a single catastrophic event. The distinctive genomic features observed in the derivative chromosomes, together with the highly characteristic junction sequences, point to non-homologous end joining (NHEJ) as being the likely underlying mutational mechanism. By contrast, replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) which involves serial replication slippage or serial template switching probably account for those complex genomic rearrangements that comprise multiple duplications and/or triplications.					NA	NA	NA
23503423	Review and Opinion			Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada	Wyatt AW, Mo F, Wang Y, Collins CC	The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing	Asian J Androl	2013 May	Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer 'omics', including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.	Homo sapiens				NA	NA	NA
21716293	Review and Opinion			The Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA	Stevens JB, Abdallah BY, Liu G, Ye CJ, Horne SD, Wang G, Savasan S, Shekhar M, Krawetz SA, Huttemann M, Tainsky MA, Wu GS, Xie Y, Zhang K, Heng HH	Diverse system stresses: common mechanisms of chromosome fragmentation	Cell Death Dis	2011 Jun	Chromosome fragmentation (C-Frag) is a newly identified MCD (mitotic cell death), distinct from apoptosis and MC (mitotic catastrophe). As different molecular mechanisms can induce C-Frag, we hypothesize that the general mechanism of its induction is a system response to cellular stress. A clear link between C-Frag and diverse system stresses generated from an array of molecular mechanisms is shown. Centrosome amplification, which is also linked to diverse mechanisms of stress, is shown to occur in association with C-Frag. This led to a new model showing that diverse stresses induce common, MCD. Specifically, different cellular stresses target the integral chromosomal machinery, leading to system instability and triggering of MCD by C-Frag. This model of stress-induced cell death is also applicable to other types of cell death. The current study solves the previously confusing relationship between the diverse molecular mechanisms of chromosome pulverization, suggesting that incomplete C-Frag could serve as the initial event responsible for forms of genome chaos including chromothripsis. In addition, multiple cell death types are shown to coexist with C-Frag and it is more dominant than apoptosis at lower drug concentrations. Together, this study suggests that cell death is a diverse group of highly heterogeneous events that are linked to stress-induced system instability and evolutionary potential.					NA	NA	NA
22811041	Review and Opinion			Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Physiology, the University of Manitoba, Winnipeg, Canada	Righolt C, Mai S	Shattered and stitched chromosomes-chromothripsis and chromoanasynthesis-manifestations of a new chromosome crisis?	Genes Chromosomes Cancer	2012 Nov	Chromothripsis (chromosome shattering) has been described as complex rearrangements affecting single chromosome(s) in one catastrophic event. The chromosomes would be shattered and stitched together during this event. This phenomenon is proposed to constitute the basis for complex chromosomal rearrangements seen in 2-3% of all cancers and in ~25% of bone cancers. Here we discuss chromothripsis, the use of this term and the evidence presented to support a single catastrophic event that remodels the genome in one step. We discuss why care should be taken in using the term chromothripsis and what evidence is lacking to support its use while describing complex rearrangements.					NA	NA	NA
25106763	Review and Opinion	Prostate cancer		Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland	Mehine M, Makinen N, Heinonen HR, Aaltonen LA, Vahteristo P	Genomics of uterine leiomyomas: insights from high-throughput sequencing.	Fertil Steril	2014 Sep	Uterine leiomyomas are benign smooth-muscle tumors of extremely low malignant potential. Early work utilizing classical cytogenetics revealed that a subset of uterine leiomyomas harbor recurrent chromosomal rearrangements, such as translocations affecting the HMGA2 gene. Our understanding of the genetics of many tumor types has deepened remarkably with the emergence of next-generation sequencing technologies. Exome sequencing identified that the majority of leiomyomas display highly specific MED12 mutations. Further studies suggest that these MED12 hotspot mutations are also frequent in breast fibroadenomas, but not in other human tumors. Whole-genome sequencing showed that a subset of leiomyomas display complex chromosomal rearrangements resembling chromothripsis. These were formed in a single event of chromosomal breakage and random reassembly involving one or a limited number of chromosomes. Although most leiomyomas have been shown to arise independently, these studies also revealed that distinct nodules within a uterus may display identical genetic changes indicating a common clonal origin. A minority of leiomyomas were also found to display deletions within the COL4A5-COL4A6 genes, leading to upregulation of the adjacent gene IRS4. The findings derived from high-throughput sequencing combined with previous knowledge have led to an emerging molecular classification of leiomyomas, suggesting that there are several distinct pathogenic pathways involved in leiomyoma formation. The evidence points to at least 4 molecular subclasses: leiomyomas with MED12 mutation, FH inactivation, HMGA2 overexpression, and COL4A6-COL4A5 deletion. Elucidating the molecular pathogenesis of leiomyomas should be relevant for developing treatments for this very common disease.					NA	NA	NA
24931269	Review and Opinion			Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany	Tapia-Laliena MA, Korzeniewski N, Hohenfellner M, Duensing S	High-risk prostate cancer: a disease of genomic instability.	Urol Oncol	2014 Nov	OBJECTIVES: In this review, we will discuss the latest advances in our understanding of the relationship between the cellular DNA damage response and genomic instability in prostate cancer and the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management. METHODS: Important findings related to genomic instability in prostate cancer were retrieved from the literature and combined with our own results and a translational perspective. RESULTS: Prostate cancer is characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations (CNAs), gene fusions, complex chromosomal rearrangements, and aneuploidy. In addition, massive DNA damaging events, including chromothripsis and chromoplexy, which can lead to extensive genomic insults in a single step, have been identified. A number of these genomic aberrations have been found to provide prognostic information and can therefore help to identify high-risk patients. In addition, defects in the DNA damage checkpoint and repair machinery can potentially be harnessed for therapeutic purposes. CONCLUSIONS: Genomic instability plays a crucial role in the malignant progression of prostate cancer and can be exploited for the development of novel prognostic biomarkers and innovative therapies.					NA	NA	NA
24563343	Review and Opinion	Myelodysplastic syndrome		Department of Pathology, University of Massachusetts Memorial Medical Center, RM 213, Biotech 3, 1 Innovation Dr, Worcester, MA, 01605, USA	Fischer AH	The diagnostic pathology of the nuclear envelope in human cancers.	Adv Exp Med Biol	2014	Cancer is still diagnosed on the basis of altered tissue and cellular morphology. The criteria that pathologists use for diagnosis include many morphologically distinctive alterations in the nuclear envelope (NE). With the expectation that diagnostic NE changes will have biological relevance to cancer, a classification of the various types of NE structural changes into three groups is proposed. The first group predicts chromosomal instability. The changes in this group include pleomorphism of lamina size and shape, as if constraints to maintain a spherical shape were lost. Also characteristic of chromosomal instability are the presence of micronuclei, a specific structural feature likely related to the newly described physiology of chromothripsis. The second group is predicted to be functionally important during clonal evolution, because the NE changes in this group are conserved during the clonal evolution of genetically unstable tumors. Two examples of this group include increased ratio of nuclear volume to cytoplasmic volume and the relatively fragile nuclei of small-cell carcinomas. The third and most interesting group develops in a near-diploid, genetically stable background. Many of these (perhaps ultimately all) are directly related to the activation of particular oncogenes. The changes in this group so far include long inward folds of the NE and spherical invaginations of cytoplasm projecting partially into the nucleus (intranuclear cytoplasmic inclusions). This group is exemplified by papillary thyroid carcinoma in which RET and TRK tyrosine kinases, and probably B-Raf mutations, directly lead to diagnostic longitudinal folds of the lamina (nuclear grooves) and intranuclear cytoplasmic inclusions. B-Raf activation may also be linked to intranuclear cytoplasmic inclusions in melanoma and to nuclear grooves in Langerhans cell histiocytosis. Nuclear grooves in granulosa cell tumor may be related to mutations in the FOXL2 oncogene. Uncovering the precise mechanistic basis for any of these lamina alterations would provide a valuable objective means for improving diagnosis, and will likely reflect new types of functional changes, relevant to particular forms of cancer.					NA	NA	NA
25369334	Review and Opinion			Institute of Biophysics, Academy of Sciences of the Czech Republic, v. v. i., Brno, Czech Republic	Pagacova E, Falk M, Falkova I, Lukasova E, Michalova K, Oltova A, Raska I, Kozubek S.	Frequent chromatin rearrangements in myelodysplastic syndromes--what stands behind?	Folia Biol (Praha)	2014	Myelodysplastic syndromes (MDS) represent a clinically and genetically heterogeneous group of clonal haematopoietic diseases characterized by a short survival and high rate of transformation to acute myeloid leukaemia (AML). In spite of this variability, MDS is associated with typical recurrent non-random cytogenetic defects. Chromosomal abnormalities are detected in the malignant bone-marrow cells of approximately 40-80 % of patients with primary or secondary MDS. The most frequent chromosomal rearrangements involve chromosomes 5, 7 and 8. MDS often shows presence of unbalanced chromosomal changes, especially large deletions [del(5), del(7q), del(12p), del(18q), del(20q)] or losses of whole chromosomes (7 and Y). The most typical cytogenetic abnormality is a partial or complete deletion of 5q- that occurs in roughly 30 % of all MDS cases either as the sole abnormality or in combination with other aberrations as a part of frequently complex karyotypes. The mechanisms responsible for the formation of MDS-associated recurrent translocations and complex karyotypes are unknown. Since some of the mentioned aberrations are characteristic for several haematological malignancies, more general cellular conditions could be expected to play a role. In this article, we introduce the most common rearrangements linked to MDS and discuss the potential role of the non-random higher-order chromatin structure in their formation. A contribution of the chromothripsis - a catastrophic event discovered only recently - is considered to explain how complex karyotypes may occur (during a single event).					NA	NA	NA
25319867	Review and Opinion			Research Division, Peter MacCallum Cancer Centre, Melbourne, 3002, Victoria, Australia	Kansara M, Teng MW, Smyth MJ, Thomas DM	Translational biology of osteosarcoma.	Nat Rev Cancer	2014 Nov	For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.					NA	NA	NA
26040249	Review and Opinion			Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont	Cannan WJ, Pederson DS	Mechanisms and Consequences of Double-strand DNA Break Formation in Chromatin.	J Cell Physiol	2015 Jun 	All organisms suffer double-strand breaks (DSBs) in their DNA as a result of exposure to ionizing radiation. DSBs can also form when replication forks encounter certain DNA lesions or repair intermediates. The processing and repair of DSBs can lead to mutations, loss of heterozygosity, and chromosome rearrangements that can lead to cell death or cancer. The most common pathway used to repair DSBs in metazoans (non-homologous DNA end joining) is more commonly mutagenic than the alternative pathway (homologous recombination mediated repair). Thus, factors that influence the choice of pathways used DSB repair can affect an individual's mutation burden and risk of cancer. This review describes radiological, chemical and biological mechanisms that generate DSBs, and discusses the impact of such variables as DSB etiology, cell type, cell cycle, and chromatin structure on the yield, distribution, and processing of DSBs. The final section will focus on nucleosome-specific mechanisms that influence DSB production, and the possible relationship between higher order chromosome coiling and chromosome shattering (chromothripsis).This article is protected by copyright. All rights reserved.					NA	NA	NA
23112751	Review and Opinion			Department of Medical Genetics, University Medical Center Utrech	Martin Poot	Chromothripsis Challenges the Germline	Mol Syndromol	2012 July	Complex chromosomal rearrangements (CCRs) con- stitute a rare, difficult to detect and hard to interpret en- tity in clinical cytogenetic diagnosis. CCRs are usually detected by inspection of chromosomal banding pat- terns during karyotyping. The sensitivity of detection is thus limited by the number of microscopically visible bands, typically in the order of 500 to 800. Array-CGH offers a dramatically improved resolution of detection but is limited to CCRs that are associated with copy number variations (CNVs), i.e. losses or gains. Copy neu- tral CCRs, in contrast, escape detection by array-CGH					NA	NA	NA
23135524	Review and Opinion			Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA	Holland AJ, Cleveland DW	Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements.	Nat Med	2012 Nov	Next-generation sequencing of DNA from human tumors or individuals with developmental abnormalities has led to the discovery of a process we term chromoanagenesis, in which large numbers of complex rearrangements occur at one or a few chromosomal loci in a single catastrophic event. Two mechanisms underlie these rearrangements, both of which can be facilitated by a mitotic chromosome segregation error to produce a micronucleus containing the chromosome to undergo rearrangement. In the first, chromosome shattering (chromothripsis) is produced by mitotic entry before completion of DNA replication within the micronucleus, with a failure to disassemble the micronuclear envelope encapsulating the chromosomal fragments for random reassembly in the subsequent interphase. Alternatively, locally defective DNA replication initiates serial, microhomology-mediated template switching (chromoanasynthesis) that produces local rearrangements with altered gene copy numbers. Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease.					NA	NA	NA
22972457	Review and Opinion			The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK	Forment JV, Kaidi A, Jackson SP	Chromothripsis and cancer: causes and consequences of chromosome shattering.	Nat Rev Cancer	2012 Oct	Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer.					NA	NA	NA
23005591	Review and Opinion			Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan	Shibata T	Cancer genomics and pathology: all together now.	Pathol Int	2012 Oct	Cancer develops from a single cell with stepwise accumulation of genomic alterations. Recent innovative sequencing technologies have made it possible to sequence the full cancer genome. Cancer genome sequencing has been productive and helpful in the discovery of novel cancer genes. It also has revealed previously unknown but intriguing features of the cancer genome such as chromothripsis and kataegis. However, careful comparison of these studies has suggested that analyses of most tumors still seem to be incomplete, and histopathological diagnosis/classification will be essential for refining these data. Based on the improvement of technology and the completion of the cancer gene catalog, genetic diagnosis, such as examination of all potentially druggable mutations, of individual cancers will be performed routinely together with histological diagnosis. Pathologists will play a central role in both interpreting these patho-molecular diagnoses for oncologists, and the process of decision-making necessary for individualized medicine.					NA	NA	NA
26178348	Review and Opinion			Department of Radiation Oncology and Molecular Radiation Sciences ; The Kimmel Cancer Center at Johns Hopkins ; Baltimore MD USA	Ivkov R, Bunz F	Pathways to chromothripsis	Cell Cycle	2015 Sep	Chromothripsis is a recently recognized mode of genetic instability that generates chromosomes with strikingly large numbers of segmental re-arrangements. While the characterization of these derivative chromosomes has provided new insights into the processes by which cancer genomes can evolve, the underlying signaling events and molecular mechanisms remain unknown. In medulloblastomas, chromothripsis has been observed to occur in the context of mutational inactivation of p53 and activation of the canonical Hedgehog (Hh) pathway. Recent studies have illuminated mechanistic links between these 2 signaling pathways, including a novel PTCH1 homolog that is regulated by p53. Here, we integrate this new pathway into a hypothetical model for the catastrophic DNA breakage that appears to trigger profound chromosomal rearrangements.	Homo sapiens				NA	NA	NA
27023493	Review and Opinion			Group Maintenance of Genome Stability, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Department of Molecular Genetics, University of Kaiserslautern, Paul-Ehrlich Str. 24, 67653 Kaiserslautern, Germany	Storchova Z, Kloosterman WP	The genomic characteristics and cellular origin of chromothripsis	Curr Opin Cell Biol	2016 Jun	Human genomes are continuously subjected to mutations, which can drive genetic diseases and cancer. An intriguing recent finding has been the discovery of chromothripsis, a spectacular and complex form of chromosome rearrangement that can occur in the genomes of cancer cells and patients with congenital diseases. Chromothripsis has been described in a large array of human cancers and various types of chromothripsis have appeared, which differ in complexity and genomic hallmarks. From the combined genomic data a consensus hypothesis has been inferred, involving aberrant DNA replication and chromosome shattering as the underlying processes explaining chromothripsis. In addition, recent work has established several cellular models that recapitulate chromothripsis under defined experimental conditions. One of these models indicates that chromothripsis can originate from DNA damage in micronuclei, providing an elegant explanation for the restriction of chromothriptic rearrangements to a single chromosome. Alternatively, chromothripsis can be caused by telomere crisis, a process that involves formation of dicentric chromosomes and chromatin bridges. Here, we summarize the genomic features of chromothripsis and we discuss experimental approaches that allow dissection of the chromothripsis process.							
27259208	Review and Opinion			Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA	Kass EM, Moynahan ME, Jasin M	When Genome Maintenance Goes Badly Awry	Mol Cell	2016 Jun	Genetic abnormalities are present in all tumor types, although the frequency and type can vary. Chromosome abnormalities include highly aberrant structures, particularly chromothriptic chromosomes. The generation of massive sequencing data has illuminated the scope of the mutational burden in cancer genomes, identifying patterns of mutations (mutation signatures), which have the potential to shed light on the relatedness and etiologies of cancers and impact therapy response. Some mutation patterns are clearly attributable to disruptions in pathways that maintain genomic integrity. Here we review recent advances in our understanding of genetic changes occurring in cancers and the roles of genome maintenance pathways.							
26726318	Review and Opinion			Department of Medicine, Division of Hematology Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA 02215	Willis NA, Rass E, Scully R	Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement	Trends Cancer	2015 Dec	Chromosome rearrangement plays a causal role in tumorigenesis by contributing to the inactivation of tumor suppressor genes, the dysregulated expression or amplification of oncogenes and the generation of novel gene fusions. Chromosome breaks are important intermediates in this process. How, when and where these breaks arise and the specific mechanisms engaged in their repair strongly influence the resulting patterns of chromosome rearrangement. Here, we review recent progress in understanding how certain distinctive features of the cancer genome, including clustered mutagenesis, tandem segmental duplications, complex breakpoints, chromothripsis, chromoplexy and chromoanasynthesis may arise.							
26703575	Review and Opinion			Institute of Immunology  and Experimental Oncology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten 58453, Germany	Dittmar T, Zanker KS	Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells	Int J Mol Sci	2015 Dec	The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that "accidental" tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells.							
26459672	Review and Opinion	WHIM syndrome		Laboratory of Molecular Immunology; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, MD USA	McDermott DH, Gao JL, Murphy PM	Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation	Rare Dis	2015 Aug	We recently reported a 59 year old female, designated WHIM-09, who was born with the rare immunodeficiency disease WHIM syndrome but underwent spontaneous phenotypic reversion as an adult. The causative WHIM mutation CXCR4 (R334X) was absent in her myeloid and erythroid lineage, but present in her lymphoid lineage and in epithelial cells, defining her as a somatic genetic mosaic. Genomic and hematologic analysis revealed chromothripsis (chromosome shattering) on one copy of chromosome 2, which deleted 164 genes including CXCR4 (R334X) in a single haematopoietic stem cell (HSC) (Fig. 1). Experiments in mice indicated that deleting one copy of Cxcr4 is sufficient to confer a selective advantage for engraftment of transplanted HSCs, suggesting a mechanism for clinical cure in WHIM-09. Genome editing may allow autologous transplantation of HSCs lacking one copy of CXCR4 without bone marrow conditioning as a general cure strategy in WHIM syndrome, safely recapitulating the outcome in patient WHIM-09. Figure 1.Chromothripsis (chromosomal shattering) resulted in clinical cure of a patient with a rare immunodeficiency (WHIM syndrome) by deleting the mutant copy of CXCR4	Homo sapiens						
26455580	Review and Opinion			Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany	Rode A, Maass KK, Willmund KV, Lichter P, Ernst A	Chromothripsis in cancer cells: An update	Int J Cancer	2016 May	In 2011, a novel form of genome instability was reported by Stephens et al., characterized by tens to hundreds of locally clustered rearrangements affecting one or a few chromosome(s) in cancer cells. This phenomenon, termed chromothripsis, is likely due to a single catastrophic event leading to the simultaneous formation of multiple double-strand breaks, which are repaired by error-prone mechanisms. Since then, the occurrence of chromothripsis was detected in a wide range of tumor entities. In this review, we will discuss potential mechanisms of chromothripsis initiation in cancer and outline the prevalence of chromothripsis across entities. Furthermore, we will examine how chromothriptic events may promote cancer development and how they may affect cancer therapy.							
26442848	Review and Opinion			Department of Pediatric Oncology	Leibowitz ML, Zhang CZ, Pellman D	Chromothripsis: A New Mechanism for Rapid Karyotype Evolution	Annu Rev Genet	2015 Oct	Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, chromothripsis, is characterized by tens or hundreds of rearrangements confined to a single chromosome or to local regions over a few chromosomes. Genomic analysis of chromothripsis and the search for its biological mechanism have led to new insights on how chromosome segregation errors can generate mutagenesis and changes to the karyotype. Here, we review the genomic features of chromothripsis and summarize recent progress on understanding its mechanism. This includes reviewing new work indicating that one mechanism to generate chromothripsis is through the physical isolation of chromosomes in abnormal nuclear structures (micronuclei). We also discuss connections revealed by recent genomic analysis of cancers between chromothripsis, chromosome bridges, and ring chromosomes.							
26366555	Review and Opinion			Division of Neuroscience , Oregon National Primate Research Center	Carbone L, Chavez SL	Mammalian pre-implantation chromosomal instability: species comparison, evolutionary considerations, and pathological correlations	Syst Biol Reprod Med	2015 Sep	Pre-implantation embryo development in mammals begins at fertilization with the migration and fusion of the maternal and paternal pro-nuclei, followed by the degradation of inherited factors involved in germ cell specification and the activation of embryonic genes required for subsequent cell divisions, compaction, and blastulation. The majority of studies on early embryogenesis have been conducted in the mouse or non-mammalian species, often requiring extrapolation of the findings to human development. Given both conserved similarities and species-specific differences, however, even comparison between closely related mammalian species may be challenging as certain aspects, including susceptibility to chromosomal aberrations, varies considerably across mammals. Moreover, most human embryo studies are limited to patient samples obtained from in vitro fertilization (IVF) clinics and donated for research, which are generally of poorer quality and produced with germ cells that may be sub-optimal. Recent technical advances in genetic, epigenetic, chromosomal, and time-lapse imaging analyses of high quality whole human embryos have greatly improved our understanding of early human embryogenesis, particularly at the single embryo and cell level. This review summarizes the major characteristics of mammalian pre-implantation development from a chromosomal perspective, in addition to discussing the technological achievements that have recently been developed to obtain this data. We also discuss potential translation to clinical applications in reproductive medicine and conclude by examining the broader implications of these findings for the evolution of mammalian species and cancer pathology in somatic cells.							
26209074	Review and Opinion			Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA	Weckselblatt B, Rudd MK	Human Structural Variation: Mechanisms of Chromosome Rearrangements	Trends Genet	2015 Oct								
28588432	Review and Opinion			Department of Human Genetics, University of Wurzburg, Biozentrum, Am Hubland, DE-97074 Wurzburg	Poot M	Of Simple and Complex Genome Rearrangements, Chromothripsis, Chromoanasynthesis, and Chromosome Chaos	Mol Syndromol	2017 May	No abstract available.							
28342454	Review and Opinion			Institut fur Pharmakologie und Toxikologie, Universitat Wurzburg, Germany; Bavarian Health and Food Safety Authority, Erlangen, Germany	Hintzsche H, Hemmann U, Poth A, Utesch D, Lott J, Stopper H; Working Group 'In vitro micronucleus test', Gesellschaft fur Umwelt-Mutationsforschung (GUM, German-speaking section of the European Environmental Mutagenesis and Genomics Society EEMGS)	Fate of micronuclei and micronucleated cells	Mutat Res	2017 Jan - Mar	The present review describes available evidence about the fate of micronuclei and micronucleated cells. Micronuclei are small, extranuclear chromatin bodies surrounded by a nuclear envelope. The mechanisms underlying the formation of micronuclei are well understood but not much is known about the potential fate of micronuclei and micronucleated cells. Many studies with different experimental approaches addressed the various aspects of the post-mitotic fate of micronuclei and micronucleated cells. These studies are reviewed here considering four basic possibilities for potential fates of micronuclei: degradation of the micronucleus or the micronucleated cell, reincorporation into the main nucleus, extrusion from the cell, and persistence in the cytoplasm. Two additional fates need to be considered: premature chromosome condensation/chromothripsis and the elimination of micronucleated cells by apoptosis, yielding six potential fates for micronuclei and/or micronucleated cells. The available data is still limited, but it can be concluded that degradation and extrusion of micronuclei might occur in rare cases under specific conditions, reincorporation during the next mitosis occurs more frequently, and the majority of the micronuclei persist without alteration at least until the next mitosis, possibly much longer. Overall, the consequences of micronucleus formation on the cellular level are still far from clear, but they should be investigated further because micronucleus formation may contribute to the initial and later steps of malignant cell transformation, by causing gain or loss of genetic material in the daughter cells and by the possibility of massive chromosome rearrangement in chromosomes entrapped within a micronucleus by the mechanisms of chromothripsis and chromoanagenesis.							
28244221	Review and Opinion			CNRS UMR 8200, Institut de Cancerologie Gustave-Roussy, Universite Paris-Saclay, Equipe Labellisee Ligue Contre le Cancer, Villejuif, France	So A, Le Guen T, Lopez BS, Guirouilh-Barbat J	Genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells	FEBS J	2017 Aug	DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to profound genome rearrangements and/or cell death. They routinely occur in genomes due to endogenous or exogenous stresses. Efficient repair systems, canonical non-homologous end-joining and homologous recombination exist in the cell and not only ensure the maintenance of genome integrity but also, via specific programmed DNA double-strand breaks, permit its diversity and plasticity. However, these repair systems need to be tightly controlled because they can also generate genomic rearrangements. Thus, when DSB repair is not properly regulated, genome integrity is no longer guaranteed. In this review, we will focus on non-programmed genome rearrangements generated by DSB repair, in somatic cells. We first discuss genome rearrangements induced by homologous recombination and end-joining. We then discuss recently described rearrangement mechanisms, driven by microhomologies, that do not involve the joining of DNA ends but rather initiate DNA synthesis (microhomology-mediated break-induced replication, fork stalling and template switching and microhomology-mediated template switching). Finally, we discuss chromothripsis, which is the shattering of a localized region of the genome followed by erratic rejoining.							
28096526	Review and Opinion			Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA	Maciejowski J, de Lange T	Telomeres in cancer: tumour suppression and genome instability	Nat Rev Mol Cell Biol	2017 Mar	The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.							
28056863	Review and Opinion			Neuroblastoma Laboratory, Italian Neuroblastoma Foundation, Pediatric Research Institute, Fondazione Citta della Speranza, Corso Stati Uniti, 4, 35127, Padua, Italy	Tonini GP	Growth, progression and chromosome instability of Neuroblastoma: a new scenario of tumorigenesis?	BMC Cancer	2017 Jan	BACKGROUND: Neuroblastoma is a pediatric cancer with a low survival rate of patients with metastatic stage 4 disease. Tumor aggressiveness and progression have been associated with structural copy number variations (CNVs) that are observed in malignant cells. In contrast, localized Neuroblastomas, which are associated with a low number of structural CNVs but frequent numerical CNVs, are less aggressive, and patients have good outcomes. Finally, whole-genome and whole-exome sequencing of Neuroblastoma tissues have shown few damaging mutations in these tumors. CONCLUSIONS: In the present report it is proposed that chromosome instability (CIN) plays a major role in Neuroblastoma tumorigenesis and that CIN is already present in the early phases of tumor development. High CIN can promote several types of chromosomal damage including chromothripsis, gene deletion, amplification and rearrangements, which deregulate gene expression. Indeed, gene rearrangements have been reported as a new scenario in the development of Neuroblastoma, which supports the hypothesis that CIN is an early step preliminary to the late catastrophic events leading to tumor development.							
28008180	Review and Opinion			Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98109, USA	Hatch EM	Y chromothripsis?	Nat Cell Biol	2016 Dec	Micronucleation of missegregated chromatin can lead to substantial chromosome rearrangements via chromothripsis. However, the molecular details of micronucleus-based chromothripsis are still unclear. Now, an elegant system that specifically induces missegregation of the Y chromosome provides insight into this process, including a role for non-homologous end joining.							
27893960	Review and Opinion			Department of Biology, Tufts University, Medford, Massachusetts 02155	McVey M, Khodaverdian VY, Meyer D, Cerqueira PG, Heyer WD	Eukaryotic DNA Polymerases in Homologous Recombination	Annu Rev Genet	2016 Nov	Homologous recombination (HR) is a central process to ensure genomic stability in somatic cells and during meiosis. HR-associated DNA synthesis determines in large part the fidelity of the process. A number of recent studies have demonstrated that DNA synthesis during HR is conservative, less processive, and more mutagenic than replicative DNA synthesis. In this review, we describe mechanistic features of DNA synthesis during different types of HR-mediated DNA repair, including synthesis-dependent strand annealing, break-induced replication, and meiotic recombination. We highlight recent findings from diverse eukaryotic organisms, including humans, that suggest both replicative and translesion DNA polymerases are involved in HR-associated DNA synthesis. Our focus is to integrate the emerging literature about DNA polymerase involvement during HR with the unique aspects of these repair mechanisms, including mutagenesis and template switching.							
27888607	Review and Opinion			Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan	Fukami M, Shima H, Suzuki E, Ogata T, Matsubara K, Kamimaki T	Catastrophic cellular events leading to complex chromosomal rearrangements in the germline	Clin Genet	2017 May	Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.							
27542123	Review and Opinion			Cell Biology Unit, Department of Cell Biology, Physiology and Immunology, Biosciences School, Universitat Autonoma de Barcelona, 08193, Bellaterra, Spain	Terradas M, Martin M, Genesca A	Impaired nuclear functions in micronuclei results in genome instability and chromothripsis	Arch Toxicol	2016 Nov	Micronuclei (MN) have generally been considered a consequence of DNA damage and, as such, have been used as markers of exposure to genotoxic agents. However, advances in DNA sequencing methods and the development of high-resolution microscopy with which to analyse chromosome dynamics in live cells have been fundamental in building a more refined view of the existing links between DNA damage and micronuclei. Here, we review recent progress indicating that defects of micronuclei affect basic nuclear functions, such as DNA repair and replication, generating massive damage in the chromatin of the MN. In addition, the physical isolation of chromosomes within MN offers an attractive mechanistic explanation for chromothripsis, a massive local DNA fragmentation that produces complex rearrangements restricted to only one or a few chromosomes. When micronuclear chromatin is reincorporated in the daughter cell nuclei, the under-replicated, damaged or rearranged micronuclear chromatin might contribute to genome instability. The traditional conception of micronuclei has been overturned, as they have evolved from passive indicators of DNA damage to active players in the formation of DNA lesions, thus unravelling previously unforeseen roles of micronuclei in the origins of chromosome instability.							
27342254	Review and Opinion			European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrabe 1, 69117 Heidelberg, Germany	Habermann N, Mardin BR, Yakneen S, Korbel JO	Using large-scale genome variation cohorts to decipher the molecular mechanism of cancer	C R Biol	2016 Jul	Characterizing genomic structural variations (SVs) in the human genome remains challenging, and there is a growing interest to understand somatic SVs occurring in cancer, a disease of the genome. A havoc-causing SV process known as chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe. Recent efforts led to the development of a set of conceptual criteria for the inference of chromothripsis events in cancer genomes and to the development of experimental model systems for studying this striking DNA alteration process in vitro. We discuss these approaches, and additionally touch upon current Big Data efforts that employ hybrid cloud computing to enable studies of numerous cancer genomes in an effort to search for commonalities and differences in molecular DNA alteration processes in cancer.							
27208973	Review and Opinion			School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia	Reece AS, Hulse GK	Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity	Mutat Res	2016 Jul	The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern.							
27022325	Review and Opinion			Department of Human Genetics, University of Wurzburg, Biozentrum, Am Hubland, DE-97074 Wurzburg (Germany)	Poot M	From Telomere Crisis via Dicentric Chromosomes to Kataegis and Chromothripsis	Mol Syndromol	2016 Feb	No abstract available.							
26997940	Review and Opinion			Department of Human Genetics, University of Wurzburg, Biozentrum, Am Hubland, DE-97074 Wurzburg (Germany)	Poot M	Chromothripsis after Stumbling through DNA Replication	Mol Syndromol	2016 Feb	No abstract available.							
26880205	Review and Opinion			Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA	Kim S, Peterson SE, Jasin M, Keeney S	Mechanisms of germ line genome instability	Semin Cell Dev Biol	2016 Jun	During meiosis, numerous DNA double-strand breaks (DSBs) are formed as part of the normal developmental program. This seemingly destructive behavior is necessary for successful meiosis, since repair of the DSBs through homologous recombination (HR) helps to produce physical links between the homologous chromosomes essential for correct chromosome segregation later in meiosis. However, DSB formation at such a massive scale also introduces opportunities to generate gross chromosomal rearrangements. In this review, we explore ways in which meiotic DSBs can result in such genomic alterations.							
26790771	Review and Opinion			Department of Molecular Medicine, Institute of Biotechnology, United States	Sinha S, Villarreal D, Shim EY, Lee SE	Risky business: Microhomology-mediated end joining	Mutat Res	2016 Jun	Prevalence of microhomology (MH) at the breakpoint junctions in somatic and germ-line chromosomal rearrangements and in the programmed immune receptor rearrangements from cells deficient in classical end joining reveals an enigmatic process called MH-mediated end joining (MMEJ). MMEJ repairs DNA double strand breaks (DSBs) by annealing flanking MH and deleting genetic information at the repair junctions from yeast to humans. Being genetically distinct from canonical DNA DSB pathways, MMEJ is involved with the fusions of eroded/uncapped telomeres as well as with the assembly of chromosome fragments in chromothripsis. In this review article, we will discuss an up-to-date model representing the MMEJ process and the mechanism by which cells regulate MMEJ to limit repair-associated mutagenesis. We will also describe the possible therapeutic gains resulting from the inhibition of MMEJ in recombination deficient cancers. Lastly, we will embark on two contentious issues associated with MMEJ such as the significance of MH at the repair junction to be the hallmark of MMEJ and the relationship of MMEJ to other mechanistically related DSB repair pathways.							
26590822	Review and Opinion			Department of Cell, Developmental & Cancer Biology, Graduate Program in Molecular & Cellular Biosciences, Oregon Health & Science University School of Medicine, Portland, Ore., USA	Daughtry BL, Chavez SL	Chromosomal instability in mammalian pre-implantation embryos: potential causes, detection methods, and clinical consequences	Cell Tissue Res	2016 Jan	Formation of a totipotent blastocyst capable of implantation is one of the first major milestones in early mammalian embryogenesis, but less than half of in vitro fertilized embryos from most mammals will progress to this stage of development. Whole chromosomal abnormalities, or aneuploidy, are key determinants of whether human embryos will arrest or reach the blastocyst stage. Depending on the type of chromosomal abnormality, however, certain embryos still form blastocysts and may be morphologically indistinguishable from chromosomally normal embryos. Despite the implementation of pre-implantation genetic screening and other advanced in vitro fertilization (IVF) techniques, the identification of aneuploid embryos remains complicated by high rates of mosaicism, atypical cell division, cellular fragmentation, sub-chromosomal instability, and micro-/multi-nucleation. Moreover, several of these processes occur in vivo following natural human conception, suggesting that they are not simply a consequence of culture conditions. Recent technological achievements in genetic, epigenetic, chromosomal, and non-invasive imaging have provided additional embryo assessment approaches, particularly at the single-cell level, and clinical trials investigating their efficacy are continuing to emerge. In this review, we summarize the potential mechanisms by which aneuploidy may arise, the various detection methods, and the technical advances (such as time-lapse imaging, -omic profiling, and next-generation sequencing) that have assisted in obtaining this data. We also discuss the possibility of aneuploidy resolution in embryos via various corrective mechanisms, including multi-polar divisions, fragment resorption, endoreduplication, and blastomere exclusion, and conclude by examining the potential implications of these findings for IVF success and human fecundity.