Abstract
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.