Divergent mutational processes distinguish hypoxic and normoxic tumours
Vinayak Bhandari, Constance H. Li, Robert G. Bristow, Paul C. Boutros, Lauri A. Aaltonen, Federico Abascal, Adam Abeshouse, Hiroyuki Aburatani, David J. Adams, Nishant Agrawal, Keun Soo Ahn, Sung-Min Ahn, Hiroshi Aikata, Rehan Akbani, Kadir C. Akdemir, Hikmat Al‐Ahmadie, Sultan T. Al‐Sedairy, Fátima Al‐Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov, Adrian Ally, Kathryn Alsop, Eva G. Álvarez, Fernanda Amary, Samirkumar B. Amin, Brice Aminou, Ole Ammerpohl, Matthew J. Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparício, Elizabeth L. Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun‐ichi Ariizumi, Joshua Armenia, Laurent Arnould, L. Sylvia, Yassen Assenov, Gurnit Atwal, Sietse Aukema, J. Todd Auman, Miriam R. R. Aure, Philip Awadalla, Marta Aymerich, Gary D. Bader, Adrian Baez‐Ortega, Matthew H. Bailey, Peter J. Bailey, Miruna Balasundaram, Saianand Balu, Pratiti Bandopadhayay, Rosamonde E. Banks, Stefano Barbi, Andrew P. Barbour, Jonathan Barenboim, Jill S. Barnholtz‐Sloan, Hugh Barr, Elisabet Barrera, John M.S. Bartlett, Javier Bartolomé, Claudio Bassi, Oliver F. Bathe, Daniel Baumhoer, Prashant Bavi, Stephen B. Baylin, Wojciech Bażant, Duncan Beardsmore, Tim Beck, Sam Behjati, Andreas Behren, Beifang Niu, Cindy Bell, Sergi Beltrán, Christopher C. Benz, Andrew Berchuck, Anke Bergmann, Erik N. Bergstrom, Benjamin P. Berman, Daniel M. Berney, Stephan H. Bernhart, Rameen Beroukhim, Mario Berríos, Samantha Bersani, Johanna Bertl, Miguel Betancourt, Vinayak Bhandari, Shriram G. Bhosle, Andrew V. Biankin, Matthias Bieg, Darell D. Bigner, Hans Binder, Ewan Birney, Michael J. Birrer, Nidhan K. Biswas, Bodil Bjerkehagen
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.