PT  - JOURNAL ARTICLE
AU  - Lina Sieverling
AU  - Chen Hong
AU  - Sandra D. Koser
AU  - Philip Ginsbach
AU  - Kortine Kleinheinz
AU  - Barbara Hutter
AU  - Delia M. Braun
AU  - Isidro Cortés-Ciriano
AU  - Ruibin Xi
AU  - Rolf Kabbe
AU  - Peter J. Park
AU  - Roland Eils
AU  - Matthias Schlesner
AU  - Karsten Rippe
AU  - David T.W. Jones
AU  - Benedikt Brors
AU  - Lars Feuerbach
AU  - PCAWG-1, PCAWG-2, PCAWG-3, PCAWG-6, PCAWG-11, PCAWG-tech
TI  - Genomic footprints of activated telomere maintenance mechanisms in cancer
AID  - 10.1101/157560
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 157560
4099  - http://biorxiv.org/content/early/2017/06/30/157560.short
4100  - http://biorxiv.org/content/early/2017/06/30/157560.full
AB  - Unlimited replicative potential is a hallmark of cancer. It requires the maintenance of telomere repeats either by telomerase activation or by an alternative lengthening of telomeres (ALT) pathway. Here, we dissected whole-genome sequencing data of 2,519 matched tumor-control samples from 36 different tumor types to characterize the genomic footprints of these telomere maintenance mechanisms. While the telomere content of tumors with ALT-associated mutations was increased, tumors with putative telomerase activation showed a moderate decrease of telomere content. A systematic search discovered 2,683 somatic integrations of telomeric sequences into non-telomeric DNA. These telomere insertions were distributed across the genome and strongly correlated with increased telomere content, genomic breakpoint frequency and ALT-associated mutations. Moreover, ALT-associated mutations were significantly linked to telomere variant repeats, especially if embedded in canonical TTAGGG telomere repeats. This includes a previously undescribed accumulation of TTCGGG. Overall, our findings provide new insight into the recurrent genomic alterations that are associated with the establishment of different telomere maintenance mechanisms in tumors.