Genomic footprints of activated telomere maintenance mechanisms in cancer
Lina Sieverling, Chen Hong, Sandra D. Koser, Philip Ginsbach, Kortine Kleinheinz, Barbara Hutter, Delia M. Braun, Isidro Cortés‐Ciriano, Ruibin Xi, Rolf Kabbe, Peter J. Park, Roland Eils, Matthias Schlesner, PCAWG-Structural Variation Working Group, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Rameen Beroukhim, 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 T. W. 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 Rodríguez–Martín, 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, Benedikt Brors, Karsten Rippe, David T. W. Jones, Lars Feuerbach, Lauri A. Aaltonen, Federico Abascal, Adam Abeshouse, Hiroyuki Aburatani, David J. Adams, Nishant Agrawal, Keun Soo Ahn, Sung-Min Ahn, Hiroshi Aikata, Rehan Akbani
Abstract
Abstract Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX trunc ) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX trunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.