Genomic footprints of activated telomere maintenance mechanisms in cancer

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/DAXX trunc) 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/DAXX trunc 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.

Non-invasive assessment of telomere maintenance mechanisms in brain tumors

“…As a result, the World Health Organization 2016 classification scheme includes molecular features to guide clinical decision-making 64 . Among the molecular features that define low-grade gliomas, mutually exclusive mutations in the TERT promoter and ATRX , which define LGOGs and LGAs, respectively 4 , 10 , 64 , are notable because they both lead to TMMs. However, non-invasive methods of detecting TMM status are lacking.…”

“…In contrast to LGOGs, low-grade astrocytomas (LGAs) activate a TERT-independent, homologous recombination-mediated mechanism of new telomeric DNA synthesis known as the alternative lengthening of telomeres (ALT) pathway 8 – 10 . Loss-of-function mutations in the chromatin remodeling protein, alpha-thalassemia/mental retardation syndrome X-linked ( ATRX ), which occur in the majority of LGAs, are associated with induction of the ALT pathway, and ATRX re-expression has been shown to repress the ALT pathway 4 , 11 – 13 .…”

Inferring Telomerase Enzymatic Activity from Expression Data

“…However, telomerase preferentially acts on the shortest telomeres 5 . Furthermore, a recent study suggests telomeric repeats can frequently insert in non-telomeric regions of the genome 78 . Thus, overall telomeric repeat counts may not precisely measure a tumor's telomere lengths.…”

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

“…Results of the algorithm based on sequencing data generated by the Illumina X10 and other sequencing platforms does not demonstrate this pattern and can be relied upon. For this analysis we favoured TelomereHunter which is well established method used in tumour sequencing analyses 68 , shows good concordance with other methods of telomere length estimation 69 and is reliable across all tested samples sequenced on the Illumina NovaSeq platform.…”