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Bhandari, Vinayak; Li, Constance H.; Bristow, Robert G.; Boutros, Paul C.; Aaltonen, Lauri A.; Abascal, Federico; Abeshouse, Adam; Aburatani, Hiroyuki; Adams, David J.; Agrawal, Nishant; Ahn, Keun Soo; Ahn, Sung-Min; Aikata, Hiroshi; Akbani, Rehan; Akdemir, Kadir C.; Al-Ahmadie, Hikmat; Al-Sedairy, Sultan T.; Al-Shahrour, Fatima; Alawi, Malik; Albert, Monique; Aldape, Kenneth; Alexandrov, Ludmil B.; Ally, Adrian; Alsop, Kathryn; [...]

Divergent mutational processes distinguish hypoxic and normoxic tumours

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  • Media type: E-Article
  • Title: Divergent mutational processes distinguish hypoxic and normoxic tumours
  • Contributor: Bhandari, Vinayak; Li, Constance H.; Bristow, Robert G.; Boutros, Paul C.; Aaltonen, Lauri A.; Abascal, Federico; Abeshouse, Adam; Aburatani, Hiroyuki; Adams, David J.; Agrawal, Nishant; Ahn, Keun Soo; Ahn, Sung-Min; Aikata, Hiroshi; Akbani, Rehan; Akdemir, Kadir C.; Al-Ahmadie, Hikmat; Al-Sedairy, Sultan T.; Al-Shahrour, Fatima; Alawi, Malik; Albert, Monique; Aldape, Kenneth; Alexandrov, Ludmil B.; Ally, Adrian; Alsop, Kathryn; [...]
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-019-14052-x
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>TP53</jats:italic>, <jats:italic>MYC</jats:italic> and <jats:italic>PTEN</jats:italic> are enriched in hypoxic tumours, and mutations in <jats:italic>PTEN</jats:italic> interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.</jats:p>
  • Access State: Open Access