Divergent mutational processes distinguish hypoxic and normoxic tumours

PCAWG Consortium

doi:10.1038/s41467-019-14052-x

Divergent mutational processes distinguish hypoxic and normoxic tumours

PCAWG Consortium

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

90 Scopus citations

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.

Original language	English
Article number	737
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14052-x
State	Published - 5 Feb 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

The authors gratefully thank Dr. Marianne Koritzinsky for insightful suggestions and thank Jenna E. van Leeuwen for visualization support. The authors also thank all members of the Boutros and Bristow labs for helpful suggestions. We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonised variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects. This study was conducted with the support of Movember funds through Prostate Cancer Canada, and with the additional support of the Ontario Institute for Cancer Research, funded by the Government of Ontario. This work was supported by Prostate Cancer Canada and is proudly funded by the Movember Foundation Team Grant T2013 and #RS2014-01. Paul C. Boutros was supported by a Terry Fox Research Institute New Investigator Award, a Prostate Cancer Canada Rising Star Fellowship, a CIHR New Investigator Award, a CIHR Project Grant, the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-125), Canadian Cancer Society (grant #705649) and by the University of California. This work has been funded by a fellowship from the Canadian Institutes of Health Research to Vinayak Bhandari. Constance Li was supported by an award from the Government of Ontario. The authors gratefully thank the Princess Margaret Cancer Centre Foundation and Radiation Medicine Programme Academic Enrichment Fund for support (to Robert G. Bristow). This work was supported by a Terry Fox Research Institute Programme Project Grant. Robert G. Bristow is a recipient of a Canadian Cancer Society Research Scientist Award. Laboratory work for R.G.B is supported by the CRUK Manchester Institute through Cancer Research UK. This work was supported by the NIH/NCI through award number P30CA016042.

Funders	Funder number
CRUK Manchester Institute
Movember Foundation Team	T2013, 2014-01
Prostate Cancer Canada Rising Star Fellowship
National Institutes of Health
National Cancer Institute	P30CA016672, P30CA016042
University of California
Movember Foundation	RS2014-01
Genome Canada
Princess Margaret Cancer Foundation
Ontario Institute for Cancer Research
Government of Ontario
Canadian Cancer Society Research Institute	705649
Government of Canada
Canadian Institutes of Health Research
Ontario Genomics Institute	OGI-125
Prostate Cancer Canada
Cancer Research UK
Canadian Cancer Society
Terry Fox Research Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-14052-x

Cite this

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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.",

author = "{PCAWG Consortium} and Vinayak Bhandari and Li, {Constance H.} and Bristow, {Robert G.} and Boutros, {Paul C.} and Aaltonen, {Lauri A.} and Federico Abascal and Adam Abeshouse and Hiroyuki Aburatani and Adams, {David J.} and Nishant Agrawal and Ahn, {Keun Soo} and Ahn, {Sung Min} and Hiroshi Aikata and Rehan Akbani and Akdemir, {Kadir C.} and Hikmat Al-Ahmadie and Al-Sedairy, {Sultan T.} and Fatima Al-Shahrour and Malik Alawi and Monique Albert and Kenneth Aldape and Alexandrov, {Ludmil B.} and Adrian Ally and Kathryn Alsop and Alvarez, {Eva G.} and Fernanda Amary and Amin, {Samirkumar B.} and Brice Aminou and Ole Ammerpohl and Anderson, {Matthew J.} and Yeng Ang and Davide Antonello and Pavana Anur and Samuel Aparicio and Appelbaum, {Elizabeth L.} and Yasuhito Arai and Axel Aretz and Koji Arihiro and Ariizumi, {Shun ichi} and Joshua Armenia and Laurent Arnould and Sylvia Asa and Yassen Assenov and Gurnit Atwal and Sietse Aukema and Auman, {J. Todd} and Aure, {Miriam R.R.} and Philip Awadalla and Marta Aymerich and Milana Frenkel-Morgenstern",

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AU - Alawi, Malik

AU - Albert, Monique

AU - Aldape, Kenneth

AU - Alexandrov, Ludmil B.

AU - Ally, Adrian

AU - Alsop, Kathryn

AU - Alvarez, Eva G.

AU - Amary, Fernanda

AU - Amin, Samirkumar B.

AU - Aminou, Brice

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AU - Aure, Miriam R.R.

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Divergent mutational processes distinguish hypoxic and normoxic tumours

Abstract

Bibliographical note

Funding

UN SDGs

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