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, Benedikt Brors, Karsten Rippe, David T. W. Jones and Lars Feuerbach ()
Additional contact information
Lina Sieverling: German Cancer Research Center (DKFZ)
Chen Hong: German Cancer Research Center (DKFZ)
Sandra D. Koser: German Cancer Research Center (DKFZ)
Philip Ginsbach: German Cancer Research Center (DKFZ)
Kortine Kleinheinz: German Cancer Research Center (DKFZ)
Barbara Hutter: German Cancer Consortium (DKTK)
Delia M. Braun: Heidelberg University
Isidro Cortés-Ciriano: Harvard Medical School
Ruibin Xi: Peking University
Rolf Kabbe: German Cancer Research Center (DKFZ)
Peter J. Park: Harvard Medical School
Roland Eils: German Cancer Research Center (DKFZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Benedikt Brors: German Cancer Research Center (DKFZ)
Karsten Rippe: German Cancer Research Center (DKFZ) and BioQuant
David T. W. Jones: Hopp Children’s Cancer Center (KiTZ)
Lars Feuerbach: German Cancer Research Center (DKFZ)

Nature Communications, 2020, vol. 11, issue 1, 1-13

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.

Date: 2020
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DOI: 10.1038/s41467-019-13824-9

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