Abstract
Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
Highlights
Many primary tumours have low levels of molecular oxygen, and hypoxic tumours respond poorly to therapy
We compiled a cohort of 1188 tumours from 27 cancer types via the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium
To determine whether genomic instability arising from specific mutational classes is associated with hypoxia, we looked to identify hypoxiaassociated pan-cancer mutational density and summary features[33]
Summary
Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Co-presence of tumour hypoxia and high genomic instability[14,15], specific cellular morphologies like intraductal and cribriform carcinoma[24] or specific mutations like loss of PTEN16, synergistically predict for rapid relapse after definitive local therapy in some tumour types, prostate cancer. These data underscore the relationship between hypoxia and DNA repair defects, and suggest the tumour microenvironment applies a selective pressure leading to the development of specific genomic profiles. Genome sequencing data was aggregated by the Pan-Cancer Analysis of
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