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Journal ArticleDOI

Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

01 Dec 2013-Genes & Development (Cold Spring Harbor Laboratory Press)-Vol. 27, Iss: 23, pp 2513-2530
TL;DR: The impact of massive chromosomal change for the development of diseases such as cancer and for evolution more generally is considered and current models for underlying mechanisms are summarized.
Abstract: 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.

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Citations
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Journal Article
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

2,737 citations

Journal ArticleDOI
10 Oct 2014-Science
TL;DR: 25 spatially distinct regions from seven operable NSCLCs were sequenced and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification, and pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity.
Abstract: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

971 citations


Cites background from "Chromothripsis and beyond: rapid ge..."

  • ...This lesion pattern is consistent with chromoanagenesis (25), and indicates a punctuated evolution pattern where multiple oncogenic events may occur simultaneously (26)....

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Journal ArticleDOI
09 Feb 2017-Cell
TL;DR: Recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution are reviewed.

919 citations


Cites background from "Chromothripsis and beyond: rapid ge..."

  • ..., 2016; Sima and Gilbert, 2014), including those that may arise through a single catastrophic event (Baca et al., 2013; Zhang et al., 2013)....

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  • ...Examples include chromothripsis, in which amassive rearrangement was acquired in a single event, and chromoplexy, which involves coordinate and simultaneous rearrangements of multiple chromosomes (Zhang et al., 2013)....

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  • ...…stark contrast to substitution mutations, which are predominant in heterochromatin, rearrangements are enriched in early replicating regions (Morganella et al., 2016; Sima and Gilbert, 2014), including those that may arise through a single catastrophic event (Baca et al., 2013; Zhang et al., 2013)....

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Journal ArticleDOI
11 Jun 2015-Nature
TL;DR: It is demonstrated that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis.
Abstract: Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.

899 citations

Journal ArticleDOI
TL;DR: This Review considers DSB repair-pathway choice in somatic mammalian cells as a series of ‘decision trees’, and explores how defective pathway choice can lead to genomic instability.
Abstract: The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of 'decision trees', and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the 'rules' governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs.

713 citations

References
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Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations


"Chromothripsis and beyond: rapid ge..." refers background in this paper

  • ...Genome instability is not only a hallmark but also an enabling characteristic of cancer (Negrini et al. 2010; Hanahan and Weinberg 2011; Gordon et al. 2012)....

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  • ...By chance, these somatic alterations in the genome will hit cancer genes—disrupting tumor suppressors or activating proto-oncogenes—affecting cells and causing their progeny to gradually accumulate the necessary ‘‘hallmarks of cancer’’ (Hanahan and Weinberg 2011)....

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Journal ArticleDOI
Ludmil B. Alexandrov1, Serena Nik-Zainal2, Serena Nik-Zainal3, David C. Wedge1, Samuel Aparicio4, Sam Behjati1, Sam Behjati5, Andrew V. Biankin, Graham R. Bignell1, Niccolo Bolli1, Niccolo Bolli5, Åke Borg2, Anne Lise Børresen-Dale6, Anne Lise Børresen-Dale7, Sandrine Boyault8, Birgit Burkhardt8, Adam Butler1, Carlos Caldas9, Helen Davies1, Christine Desmedt, Roland Eils5, Jorunn E. Eyfjord10, John A. Foekens11, Mel Greaves12, Fumie Hosoda13, Barbara Hutter5, Tomislav Ilicic1, Sandrine Imbeaud14, Sandrine Imbeaud15, Marcin Imielinsk14, Natalie Jäger5, David T. W. Jones16, David T. Jones1, Stian Knappskog17, Stian Knappskog11, Marcel Kool11, Sunil R. Lakhani18, Carlos López-Otín18, Sancha Martin1, Nikhil C. Munshi19, Nikhil C. Munshi20, Hiromi Nakamura13, Paul A. Northcott16, Marina Pajic21, Elli Papaemmanuil1, Angelo Paradiso22, John V. Pearson23, Xose S. Puente18, Keiran Raine1, Manasa Ramakrishna1, Andrea L. Richardson20, Andrea L. Richardson22, Julia Richter22, Philip Rosenstiel22, Matthias Schlesner5, Ton N. Schumacher24, Paul N. Span25, Jon W. Teague1, Yasushi Totoki13, Andrew Tutt24, Rafael Valdés-Mas18, Marit M. van Buuren25, Laura van ’t Veer26, Anne Vincent-Salomon27, Nicola Waddell23, Lucy R. Yates1, Icgc PedBrain24, Jessica Zucman-Rossi14, Jessica Zucman-Rossi15, P. Andrew Futreal1, Ultan McDermott1, Peter Lichter24, Matthew Meyerson14, Matthew Meyerson20, Sean M. Grimmond23, Reiner Siebert22, Elias Campo28, Tatsuhiro Shibata13, Stefan M. Pfister11, Stefan M. Pfister16, Peter J. Campbell3, Peter J. Campbell29, Peter J. Campbell30, Michael R. Stratton31, Michael R. Stratton3 
22 Aug 2013-Nature
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

7,904 citations


"Chromothripsis and beyond: rapid ge..." refers background in this paper

  • ...Similarly, localized regions of hypermutation (‘‘kataegis’’) that often occurred at the site of somatic rearrangements were discovered in breast cancer genomes (Nik-Zainal et al. 2012; Alexandrov et al. 2013)....

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Journal ArticleDOI
09 Oct 2009-Science
TL;DR: Hi-C is described, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing and demonstrates the power of Hi-C to map the dynamic conformations of entire genomes.
Abstract: We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

7,180 citations


"Chromothripsis and beyond: rapid ge..." refers background in this paper

  • ...…for the abnormalities of chromoanasynthesis: There is evidence that breakpoint ends of copy number abnormalities tend to be in physical proximity (Lieberman-Aiden et al. 2009; De and Michor 2011; Fudenberg et al. 2011); hence, different template-switching events could have occurred in loosely…...

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Journal ArticleDOI
29 Mar 2013-Science
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
Abstract: Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

6,441 citations

Journal ArticleDOI
01 Oct 1976-Science
TL;DR: Each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment, which should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
Abstract: It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.

6,179 citations


"Chromothripsis and beyond: rapid ge..." refers background in this paper

  • ...The evolution of a normal cell to a cancer cell is generally thought of as a sequential accumulation of many independent lesions to the genome (Nowell 1976; Greaves and Maley 2012; Yates and Campbell 2012)....

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