Genomic footprints of activated telomere maintenance mechanisms in cancer

PCAWG-Structural Variation Working Group, PCAWG Consortium

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish
Article number733
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 5 Feb 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

We thank J. Kerssemakers, M. Prinz, and M. Heinold for their help in data processing. We thank I. Buchhalter for annotation of simple nucleotide variations. We thank D. Hübschmann for his support in correlation analysis. We thank all TelNet curators for sharing the results of their extensive literature research. We thank K.I. Deeg, P. Lichter, and S.M. Pfister for their support in early stages of the study. We thank I. Chung for comments and discussion. The work was supported by grants from the German Federal Ministry of Education and Research (BMBF) within the e:Med program (project Can-cerTelSys, 01ZX1302 to K.R.) and the program for medical genome research (01KU1001A, -B, -C, and -D; 01KU1505A). S.D.K. received funding from the German Research Foundation (DFG) in research priority program SPP1463 (grant no. Br3535/1-2). I.C.C. has received funding from the European Union’s Framework Programme For Research and Innovation Horizon 2020 (2014–2020) under the Marie Sklodowska-Curie Grant Agreement No. 703543. We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment, and harmonised variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.

FundersFunder number
National Cancer InstituteP30CA016672
Horizon 2020 Framework Programme
Deutsche ForschungsgemeinschaftBr3535/1-2
Bundesministerium für Bildung und Forschung01KU1001A, 01KU1505A, 01ZX1302
Horizon 2020703543
program for medical genome research

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