Chromothripsis drives the evolution of gene amplification in cancer.
Ofer Shoshani,Simon F. Brunner,Rona Yaeger,Peter Ly,Yael Nechemia-Arbely,Dong Hyun Kim,Rongxin Fang,Guillaume A. Castillon,Miao Yu,Julia S. Z. Li,Ying Sun,Mark H. Ellisman,Bing Ren,Peter J. Campbell,Peter J. Campbell,Don W. Cleveland +15 more
TLDR
In this paper, the authors used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).Abstract:
Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1–3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage–fusion–bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions. Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.read more
Citations
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Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration
Keiko Akagi,David Eric Symer,Medhat Mahmoud,Bo Jiang,Sara Goodwin,Dara Wangsa,Zhengke Li,Weihong Xiao,Joe Dan Dunn,Thomas Ried,Kevin R. Coombes,Fritz J. Sedlazeck,Maura L. Gillison +12 more
TL;DR: The data indicate that circacatena is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
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Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia
June Takeda,Kenichi Yoshida,Masahiro Nakagawa,Yasuhito Nannya,Akinori Yoda,Ryunosuke Saiki,Yotaro Ochi,Lanying Zhao,Rurika Okuda,Xingxing Qi,Takuto Mori,Ayana Kon,Kenichi Chiba,Hiroko Tanaka,Yuichi Shiraishi,Ming-Chung Kuo,Cassandra M Kerr,Yasunobu Nagata,Daisuke Morishita,Nobuhiro Hiramoto,Akira Hangaishi,Hideyuki Nakazawa,Ken Ishiyama,Satoru Miyano,Shigeru Chiba,Yasushi Miyazaki,Toshiyuki Kitano,Kensuke Usuki,Nobuo Sezaki,Hisashi Tsurumi,Shuichi Miyawaki,Jaroslaw P. Maciejewski,Takayuki Ichikawa,Kazuma Ohyashiki,Arnold Ganser,Michael Heuser,Felicitas Thol,Lee Yung Shih,Akifumi Takaori-Kondo,Hideki Makishima,Seishi Ogawa +40 more
TL;DR: A high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia, is found, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.
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Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus
Jens Luebeck,Alvin Wei Tian Ng,Patricia C. Galipeau,Xiaohong Li,Carissa A. Sanchez,Annalise Katz-Summercorn,Hoon Kim,Sriganesh Jammula,Yudou He,Scott M. Lippman,Roel G.W. Verhaak,Carlo C. Maley,Ludmil B. Alexandrov,Brian J. Reid,Rebecca C. Fitzgerald,Thomas G. Paulson,Howard Y. Chang,Sihan Wu,Vineet Bafna,Paul S. Mischel +19 more
TL;DR: In this article , the authors analyzed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's o esophagus and found that the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage and late-stage (43%) EAC.
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Cancer Genomic Rearrangements and Copy Number Alterations from Errors in Cell Division
TL;DR: In this paper , the authors summarize the progress and survey the major unresolved questions, with particular emphasis on the relative contributions of chromosome fragmentation and DNA replication errors to complex chromosomal alterations.
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TL;DR: This paper found that misaligned chromosomes are more common than lagging chromosomes and represent a major source of chromosome instability in primary and metastatic breast cancer cells, and showed that these chromosomes predominate, and are less immunostimulatory than other chromosome segregation errors.
References
More filters
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
Fiji: an open-source platform for biological-image analysis
Johannes Schindelin,Ignacio Arganda-Carreras,Erwin Frise,Verena Kaynig,Mark Longair,Tobias Pietzsch,Stephan Preibisch,Curtis Rueden,Stephan Saalfeld,Benjamin Schmid,Jean-Yves Tinevez,Daniel J. White,Volker Hartenstein,Kevin W. Eliceiri,Pavel Tomancak,Albert Cardona +15 more
TL;DR: Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis that facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system.
Journal ArticleDOI
A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Suhas S.P. Rao,Miriam H. Huntley,Neva C. Durand,Elena K. Stamenova,Ivan D. Bochkov,James T. Robinson,James T. Robinson,Adrian L. Sanborn,Ido Machol,Ido Machol,Arina D. Omer,Arina D. Omer,Eric S. Lander,Eric S. Lander,Eric S. Lander,Erez Lieberman Aiden +15 more
TL;DR: In situ Hi-C is used to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types, identifying ∼10,000 loops that frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species.
Journal ArticleDOI
Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting
Tomas Cermak,Erin L. Doyle,Michelle Christian,Li-Li Wang,Yong Zhang,Clarice Schmidt,Joshua A. Baller,Nikunj V. Somia,Adam J. Bogdanove,Daniel F. Voytas +9 more
TL;DR: A method and reagents for efficiently assembling TALEN constructs with custom repeat arrays are presented and design guidelines based on naturally occurring TAL effectors and their binding sites are described.
Journal ArticleDOI
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
Philip J. Stephens,Christopher Greenman,Beiyuan Fu,Fengtang Yang,Graham R. Bignell,Laura Mudie,Erin Pleasance,King Wai Lau,David Beare,Lucy Stebbings,Stuart McLaren,Meng-Lay Lin,David J. McBride,Ignacio Varela,Serena Nik-Zainal,Catherine Leroy,Mingming Jia,Andrew Menzies,Adam Butler,Jon W. Teague,Michael A. Quail,John Burton,Harold Swerdlow,Nigel P. Carter,Laura Morsberger,Christine A. Iacobuzio-Donahue,George A. Follows,Anthony R. Green,Adrienne M. Flanagan,Adrienne M. Flanagan,Michael R. Stratton,P. Andrew Futreal,Peter J. Campbell,Peter J. Campbell +33 more
TL;DR: It is found that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis, which has important implications for the origins of genomic remodeling and temporal emergence of cancer.
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