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Genomic footprints of activated telomere maintenance mechanisms in cancer

Published version
Peer-reviewed

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Authors

Koser, Sandra D. 
Ginsbach, Philip 
Kleinheinz, Kortine 

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/DAXXtrunc) 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/DAXXtrunc 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.

Description

Keywords

Article, /631/67/69, /631/114, /692/4028/67, /45, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

11

Publisher

Nature Publishing Group UK
Sponsorship
Deutsche Forschungsgemeinschaft (German Research Foundation) (Br3535/1-2)
EC | Horizon 2020 (Horizon 2020 - Research and Innovation Framework Programme) (703543)
Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) (01ZX1302, 01KU1001A, -B, -C, and -D, 01KU1505A)