Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
Kadir C. Akdemir, Victoria T. Le, Sahaana Chandran, Yilong Li, Roel G.W. Verhaak, Rameen Beroukhim, Peter J. Campbell, Lynda Chin, Jesse R. Dixon, P. Andrew Futreal, PCAWG Structural Variation Working Group, Kadir C. Akdemir, Eva G. Álvarez, Adrian Baez‐Ortega, Paul C. Boutros, David D. L. Bowtell, Benedikt Brors, Kathleen H. Burns, Peter J. Campbell, Kin Chan, Ken Chen, Isidro Cortés‐Ciriano, Ana Dueso-Barroso, Andrew 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 Imieliński, David 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, Fábio C. P. 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, José M. C. Tubío, 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, Fátima Al‐Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov
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.