Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
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Kadir C Akdemir Victoria T Le Sahaana Chandran Yilong Li Roel G Verhaak Rameen Beroukhim Peter J Campbell Lynda Chin Jesse R Dixon P Andrew Futreal Kadir C Akdemir Eva G Alvarez Adrian Baez-Ortega Paul C Boutros David DL Bowtell Benedikt Brors Kathleen H Burns Peter J Campbell Kin Chan Ken Chen Isidro Cortés-Ciriano Ana Dueso-Barroso Andrew J Dunford Paul A Edwards Xavier Estivill Dariush Etemadmoghadam Lars Feuerbach J Lynn Fink Milana Frenkel-Morgenstern Dale W Garsed Mark Gerstein Dmitry A Gordenin David Haan James E Haber Julian M Hess Barbara Hutter Marcin Imielinski David TW Jones Young Seok Ju Marat D Kazanov Leszek J Klimczak Youngil Koh Jan O Korbel Kiran Kumar Eunjung Alice Lee Jake June-Koo Lee Yilong Li Andy G Lynch Geoff Macintyre Florian Markowetz Iñigo Martincorena Alexander Martinez-Fundichely Matthew Meyerson Satoru Miyano Hidewaki Nakagawa Fabio CP Navarro Stephan Ossowski Peter J Park John V Pearson Montserrat Puiggròs Karsten Rippe Nicola D Roberts Steven A Roberts Bernardo Rodriguez-Martin Steven E Schumacher Ralph Scully Mark Shackleton Nikos Sidiropoulos Lina Sieverling Chip Stewart David Torrents Jose MC Tubio Izar Villasante Nicola Waddell Jeremiah A Wala Joachim Weischenfeldt Lixing Yang Xiaotong Yao Sung-Soo Yoon Jorge Zamora Cheng-Zhong Zhang Lauri A Aaltonen Federico Abascal Adam Abeshouse Hiroyuki Aburatani David J Adams Nishant Agrawal Keun Soo Ahn Sung-Min Ahn Hiroshi Aikata Rehan Akbani Kadir C Akdemir Hikmat Al-Ahmadie Sultan T Al-Sedairy Fatima Al-Shahrour Malik Alawi Monique Albert Kenneth Aldape Ludmil B Alexandrov Adrian Ally Kathryn Alsop Eva G Alvarez Fernanda Amary Samirkumar B Amin Brice Aminou Ole Ammerpohl Matthew J Anderson Yeng Ang Davide Antonello Pavana Anur Samuel Aparicio Elizabeth L Appelbaum Yasuhito Arai Axel Aretz Koji Arihiro Shun-ichi Ariizumi Joshua Armenia Laurent Arnould Sylvia Asa Yassen Assenov Gurnit Atwal Sietse Aukema J Todd Auman Miriam RR Aure Philip Awadalla Marta Aymerich Gary D Bader Adrian Baez-Ortega Matthew H Bailey Peter J Bailey Miruna Balasundaram Saianand Balu Pratiti Bandopadhayay Rosamonde E Banks Stefano Barbi Andrew P Barbour Jonathan Barenboim Jill Barnholtz-Sloan Hugh Barr Elisabet Barrera John Bartlett Javier Bartolome Claudio Bassi Oliver F Bathe Daniel Baumhoer Prashant Bavi Stephen B Baylin Wojciech Bazant Duncan Beardsmore Timothy A Beck Sam Behjati Andreas Behren Beifang Niu Cindy Bell Sergi Beltran Christopher Benz Andrew Berchuck Anke K Bergmann Erik N Bergstrom Benjamin P Berman Daniel M Berney Stephan H Bernhart Rameen Beroukhim Mario Berrios Samantha Bersani Johanna Bertl Miguel Betancourt Vinayak Bhandari Shriram G Bhosle Andrew V Biankin Matthias Bieg Darell Bigner Hans Binder Ewan Birney Michael Birrer Nidhan K Biswas Bodil Bjerkehagen Tom Bodenheimer Lori Boice Giada Bonizzato Johann S De Bono Arnoud Boot Moiz S Bootwalla Ake Borg Arndt Borkhardt Keith A Boroevich Ivan Borozan Christoph Borst Marcus Bosenberg Mattia Bosio Jacqueline Boultwood Guillaume Bourque Paul C Boutros G Steven Bova David T Bowen Reanne Bowlby David DL Bowtell Sandrine Boyault Rich Boyce Jeffrey Boyd Alvis Brazma Paul Brennan Daniel S Brewer Arie B Brinkman Robert G Bristow Russell R Broaddus Jane E Brock Malcolm Brock Annegien Broeks Angela N Brooks Denise Brooks Benedikt Brors Søren Brunak Timothy JC Bruxner Alicia L Bruzos Alex Buchanan Ivo Buchhalter Christiane Buchholz Susan Bullman Hazel Burke Birgit Burkhardt Kathleen H Burns John Busanovich Carlos D Bustamante Adam P Butler Atul J Butte Niall J Byrne Anne-Lise Børresen-Dale Samantha J Caesar-Johnson Andy Cafferkey Declan Cahill Claudia Calabrese Carlos Caldas Fabien Calvo Niedzica Camacho Peter J Campbell Elias Campo Cinzia Cantù Shaolong Cao Thomas E Carey Joana Carlevaro-Fita Rebecca Carlsen Ivana Cataldo Mario Cazzola Jonathan Cebon Robert Cerfolio Dianne E Chadwick Dimple Chakravarty Don Chalmers Calvin Wing Yiu Chan Kin Chan Michelle Chan-Seng-Yue Vishal S Chandan David K Chang Stephen J 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Abstract
Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
Journal details
Journal
Nature Genetics
Volume
52
Issue number
3
Pages
294-305
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