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

Department of Internal Medicine

University of Toronto
Ontario Institute for Cancer Research
University of California at Los Angeles
University of Manchester
The Christie NHS Foundation Trust
Princess Margaret Cancer Centre
Vector Institute
University of Helsinki
Wellcome Sanger Institute
Memorial Sloan-Kettering Cancer Center
The University of Tokyo
The University of Chicago
Keimyung University
Gachon University
Hiroshima University
University of Texas MD Anderson Cancer Center
King Faisal Specialist Hospital and Research Centre
Centro Nacional de Investigaciones Oncológicas
University of Hamburg
Heinrich Pette Institute - Leibniz Institute for Experimental Virology
National Institutes of Health
University of California at San Diego
Provincial Health Services Authority
University of Melbourne
University of Santiago de Compostela
University of Vigo
Royal National Orthopaedic Hospital NHS Trust
Baylor College of Medicine
Jackson Laboratory
Kiel University
Ulm University
University of Queensland
Northern Care Alliance NHS Group
University and Hospital Trust of Verona
Oregon Health and Science University
Washington University St. Louis
University College London
National Cancer Center Japan
German Aerospace Center
Tokyo Women's Medical University
Los Alamos National Laboratory
Toronto General Hospital
Nottingham University Hospitals NHS Trust
German Cancer Research Center
University of North Carolina at Chapel Hill
University of Oslo
University of Barcelona

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

120 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 - 1 Dec 2020

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@article{08f3569f44f041c3b5d12cc13f127742,

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 Keunchil Park",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-14052-x",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - Divergent mutational processes distinguish hypoxic and normoxic tumours

AU - PCAWG Consortium

AU - Bhandari, Vinayak

AU - Li, Constance H.

AU - Bristow, Robert G.

AU - Boutros, Paul C.

AU - Aaltonen, Lauri A.

AU - Abascal, Federico

AU - Abeshouse, Adam

AU - Aburatani, Hiroyuki

AU - Adams, David J.

AU - Agrawal, Nishant

AU - Ahn, Keun Soo

AU - Ahn, Sung Min

AU - Aikata, Hiroshi

AU - Akbani, Rehan

AU - Akdemir, Kadir C.

AU - Al-Ahmadie, Hikmat

AU - Al-Sedairy, Sultan T.

AU - Al-Shahrour, Fatima

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

AU - Ammerpohl, Ole

AU - Anderson, Matthew J.

AU - Ang, Yeng

AU - Antonello, Davide

AU - Anur, Pavana

AU - Aparicio, Samuel

AU - Appelbaum, Elizabeth L.

AU - Arai, Yasuhito

AU - Aretz, Axel

AU - Arihiro, Koji

AU - Ariizumi, Shun ichi

AU - Armenia, Joshua

AU - Arnould, Laurent

AU - Asa, Sylvia

AU - Assenov, Yassen

AU - Atwal, Gurnit

AU - Aukema, Sietse

AU - Auman, J. Todd

AU - Aure, Miriam R.R.

AU - Awadalla, Philip

AU - Aymerich, Marta

AU - Park, Keunchil

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85079073682

U2 - 10.1038/s41467-019-14052-x

DO - 10.1038/s41467-019-14052-x

M3 - Article

C2 - 32024819

AN - SCOPUS:85079073682

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 737

ER -

Divergent mutational processes distinguish hypoxic and normoxic tumours

Abstract

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