Synapse - Divergent mutational processes distinguish hypoxic and normoxic tumours

Divergent mutational processes distinguish hypoxic and normoxic tumours Journal Article

Authors:	Bhandari, V.; Li, C. H.; Bristow, R. G.; Boutros, P. C.; & PCAWG Consortium
Contributors:	Abeshouse, A.; Al-Ahmadie, H.; Armenia, J.; Chen, H. W.; Davidson, N. R.; Gao, J.; Ghossein, R.; Giri, D. D.; Gundem, G.; Heins, Z.; Huse, J.; Iacobuzio-Donahue, C. A.; Kahles, A.; King, T. A.; Kundra, R.; Lehmann, K. V.; Levine, D. A.; Liu, E. M.; Ochoa, A.; Pastore, A.; Rätsch, G.; Reis-Filho, J.; Reuter, V.; Roehrl, M. H. A.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Senbabaoglu, Y.; Singer, S.; Socci, N. D.; Stark, S. G.; Vázquez-García, I.; Yellapantula, V. D.; Zhang, H.
Article Title:	Divergent mutational processes distinguish hypoxic and normoxic tumours
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. © 2020, The Author(s).
Keywords:	controlled study; human tissue; gene mutation; major clinical study; single nucleotide polymorphism; genetics; mutation; polymorphism, single nucleotide; neoplasm; neoplasms; gene; gene expression; cohort analysis; genetic association; genetic variability; genetic variation; pathology; mutational analysis; protein p53; hypoxia; tumor suppressor gene; molecular evolution; gene interaction; human genome; genes, myc; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; tumor suppressor protein p53; genomics; genome; cell hypoxia; cancer classification; tumor; oncogene c myc; tp53 protein, human; pten protein, human; tumor hypoxia; oncogene myc; genome, human; etiology; tumor microenvironment; pten gene; genomic structural variation; cancer; humans; human; article; whole genome sequencing; rna sequencing; tumor-related gene; hypoxic tumor
Journal Title:	Nature Communications
Volume:	11
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2020-02-05
Start Page:	737
Language:	English
DOI:	10.1038/s41467-019-14052-x
PUBMED:	32024819
PROVIDER:	scopus
PMCID:	PMC7002770
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85079073682&doi=10.1038%2fs41467-019-14052-x&partnerID=40&md5=44719fea24b2a783c1dabb08f83d4cbf
Notes:	Article -- Erratum issued, see DOI: 10.1038/s41467-022-32339-4 -- Export Date: 13 January 2023 -- Source: Scopus