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Divergent mutational processes distinguish hypoxic and normoxic tumours

Bhandari, Vinayak ; Li, Constance H ; Bristow, Robert G and Boutros, Paul C (2020) In Nature Communications 11.
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... (More)

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.

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Contribution to journal
publication status
published
subject
keywords
Cell Hypoxia/genetics, Genes, myc, Genome, Human, Genomic Structural Variation, Humans, Mutation, Neoplasms/genetics, PTEN Phosphohydrolase/genetics, Polymorphism, Single Nucleotide, Tumor Hypoxia/genetics, Tumor Microenvironment/genetics, Tumor Suppressor Protein p53/genetics, Whole Genome Sequencing
in
Nature Communications
volume
11
article number
737
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85079073682
  • pmid:32024819
ISSN
2041-1723
DOI
10.1038/s41467-019-14052-x
language
English
LU publication?
yes
id
79ce5783-20b3-4601-81d1-eb1ad7b83d43
date added to LUP
2023-01-05 14:14:54
date last changed
2024-06-25 15:01:19
@article{79ce5783-20b3-4601-81d1-eb1ad7b83d43,
  abstract     = {{<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 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.</p>}},
  author       = {{Bhandari, Vinayak and Li, Constance H and Bristow, Robert G and Boutros, Paul C}},
  issn         = {{2041-1723}},
  keywords     = {{Cell Hypoxia/genetics; Genes, myc; Genome, Human; Genomic Structural Variation; Humans; Mutation; Neoplasms/genetics; PTEN Phosphohydrolase/genetics; Polymorphism, Single Nucleotide; Tumor Hypoxia/genetics; Tumor Microenvironment/genetics; Tumor Suppressor Protein p53/genetics; Whole Genome Sequencing}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Divergent mutational processes distinguish hypoxic and normoxic tumours}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-14052-x}},
  doi          = {{10.1038/s41467-019-14052-x}},
  volume       = {{11}},
  year         = {{2020}},
}