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082 _ _ |a 500
100 1 _ |a Bhandari, Vinayak
|0 0000-0003-0265-0835
|b 0
245 _ _ |a Divergent mutational processes distinguish hypoxic and normoxic tumours.
260 _ _ |a [London]
|c 2020
|b Nature Publishing Group UK
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520 _ _ |a 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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650 _ 7 |a TP53 protein, human
|2 NLM Chemicals
650 _ 7 |a Tumor Suppressor Protein p53
|2 NLM Chemicals
650 _ 7 |a PTEN Phosphohydrolase
|0 EC 3.1.3.67
|2 NLM Chemicals
650 _ 7 |a PTEN protein, human
|0 EC 3.1.3.67
|2 NLM Chemicals
650 _ 2 |a Cell Hypoxia: genetics
|2 MeSH
650 _ 2 |a Genes, myc
|2 MeSH
650 _ 2 |a Genome, Human
|2 MeSH
650 _ 2 |a Genomic Structural Variation
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Neoplasms: genetics
|2 MeSH
650 _ 2 |a Neoplasms: pathology
|2 MeSH
650 _ 2 |a PTEN Phosphohydrolase: genetics
|2 MeSH
650 _ 2 |a Polymorphism, Single Nucleotide
|2 MeSH
650 _ 2 |a Tumor Hypoxia: genetics
|2 MeSH
650 _ 2 |a Tumor Microenvironment: genetics
|2 MeSH
650 _ 2 |a Tumor Suppressor Protein p53: genetics
|2 MeSH
650 _ 2 |a Whole Genome Sequencing
|2 MeSH
700 1 _ |a Li, Constance H
|0 0000-0002-5487-7225
|b 1
700 1 _ |a Bristow, Robert G
|0 0000-0002-8553-9544
|b 2
700 1 _ |a Boutros, Paul C
|0 0000-0003-0553-7520
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700 1 _ |a PCAWGConsortium
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773 _ _ |a 10.1038/s41467-019-14052-x
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|t Nature Communications
|v 11
|y 2020
|x 2041-1723
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