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; Ana Dueso-Barroso; Andrew J Dunford; Paul A. Edwards; Xavier Estivill; Dariush Etemadmoghadam

doi:10.1038/s41467-019-13824-9

GenomicsNature CommunicationsFeb 5, 2020

Peer-reviewed journal article

Genomic footprints of activated telomere maintenance mechanisms in cancer

Lina Sieverling iD, Chen Hong iD, Sandra D. Koser, Philip Ginsbach, Kortine Kleinheinz iD, Barbara Hutter iD, Delia M. Braun iD, Isidro Cortés‐Ciriano iD, Ruibin Xi iD, Rolf Kabbe iD, Peter J. Park iD, Roland Eils iD, Matthias Schlesner iD, PCAWG-Structural Variation Working Group, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Rameen Beroukhim iD, Paul C. Boutros iD, David D.L. Bowtell iD, Benedikt Brors iD, Kathleen H. Burns iD, Peter J. Campbell iD, Kin Chan iD, Ken Chen iD, , Rehan Akbani iD

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Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. We dissected whole-genome sequencing data of over 2,500 matched tumor-control samples from 36 different tumor types to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) was increased, tumors with TERT modifications showed a moderate decrease of telomere content. One quarter of all tumor samples contained somatic integrations of telomeric sequences into non-telomeric DNA. With 80% prevalence, ATRX/DAXXtrunc tumors display a 3-fold enrichment of telomere insertions. A systematic analysis of telomere composition identified aberrant telomere variant repeat (TVR) distribution as a genomic marker of ATRX/DAXXtrunc tumors. In this clinically relevant subgroup, singleton TTCGGG and TTTGGG TVRs (previously undescribed) were significantly enriched or depleted, respectively. Overall, our findings provide new insight into the recurrent genomic alterations that are associated with the establishment of different telomere maintenance mechanisms in cancer.