Genomic footprints of activated telomere maintenance mechanisms in cancer
Authors: Isidro Cortés-Ciriano
Chen Hong
Benedikt Brors
Karsten Rippe
Sandra D Koser
Roland Eils
David T W Jones
Peter J Park
Kortine Kleinheinz
Ruibin Xi
Lars Feuerbach
Lina Sieverling
PCAWG-Structural Variation Working Group
Matthias Schlesner
Philip Ginsbach
Delia M Braun
PCAWG Consortium
Barbara Hutter
Rolf Kabbe
Journal: Nature Communications (2020)
Discipline: Multidisciplinary
Keywords: Telomere maintenance mechanisms; TERT activation; alternative telomere lengthening; ATRX; DAXX loss
Affiliations: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany., Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany., Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany., Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, 69120, Heidelberg, Germany., Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioQuant, 69120, Heidelberg, Germany., Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, 02115, USA., Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK., Ludwig Center at Harvard, Boston, Massachusetts, 02115, USA., School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, 100871, China., Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany., German Cancer Consortium (DKTK), 69120, Heidelberg, Germany., Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany., Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany., Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. .

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. 

Retracted: No

PubPeer comments:
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