Divergent mutational processes distinguish hypoxic and normoxic tumours
Creators: name: Bhandari, Vinayak
name: Li, Constance H
name: Bristow, Robert G
name: Boutros, Paul C
name: Aaltonen, Lauri A
name: Abascal, Federico
name: Abeshouse, Adam
name: Aburatani, Hiroyuki
name: Adams, David J
name: Agrawal, Nishant
name: Ahn, Keun Soo
name: Ahn, Sung-Min
name: Aikata, Hiroshi
name: Akbani, Rehan
name: Akdemir, Kadir C
name: Al-Ahmadie, Hikmat
name: Al-Sedairy, Sultan T
name: Al-Shahrour, Fatima
name: Alawi, Malik
name: Albert, Monique
name: Aldape, Kenneth
name: Alexandrov, Ludmil B
name: Ally, Adrian
name: Alsop, Kathryn
name: Alvarez, Eva G
name: Amary, Fernanda
name: Amin, Samirkumar B
name: Aminou, Brice
name: Ammerpohl, Ole
name: Anderson, Matthew J
name: Ang, Yeng
name: Antonello, Davide
name: Anur, Pavana
name: Aparicio, Samuel
name: Appelbaum, Elizabeth L
name: Arai, Yasuhito
name: Aretz, Axel
name: Arihiro, Koji
name: Ariizumi, Shun-ichi
name: Armenia, Joshua
name: Arnould, Laurent
name: Asa, Sylvia
name: Assenov, Yassen
name: Atwal, Gurnit
name: Aukema, Sietse
name: Auman, J Todd
name: Aure, Miriam RR
name: Awadalla, Philip
name: Aymerich, Marta
name: Bader, Gary D
name: Baez-Ortega, Adrian
name: Bailey, Matthew H
name: Bailey, Peter J
name: Balasundaram, Miruna
name: Balu, Saianand
name: Bandopadhayay, Pratiti
name: Banks, Rosamonde E
name: Barbi, Stefano
name: Barbour, Andrew P
name: Barenboim, Jonathan
name: Barnholtz-Sloan, Jill
name: Barr, Hugh
name: Barrera, Elisabet
name: Bartlett, John
name: Bartolome, Javier
name: Bassi, Claudio
name: Bathe, Oliver F
name: Baumhoer, Daniel
name: Bavi, Prashant
name: Baylin, Stephen B
name: Bazant, Wojciech
name: Beardsmore, Duncan
name: Beck, Timothy A
name: Behjati, Sam
name: Behren, Andreas
name: Niu, Beifang
name: Bell, Cindy
name: Beltran, Sergi
name: Benz, Christopher
name: Berchuck, Andrew
name: Bergmann, Anke K
name: Bergstrom, Erik N
name: Berman, Benjamin P
name: Berney, Daniel M
name: Bernhart, Stephan H
name: Beroukhim, Rameen
name: Berrios, Mario
name: Bersani, Samantha
name: Bertl, Johanna
name: Betancourt, Miguel
name: Bhosle, Shriram G
name: Biankin, Andrew V
name: Bieg, Matthias
name: Bigner, Darell
name: Binder, Hans
name: Birney, Ewan
name: Birrer, Michael
name: Biswas, Nidhan K
name: Bjerkehagen, Bodil
name: Bodenheimer, Tom
name: Boice, Lori
name: Bonizzato, Giada
name: De Bono, Johann S
name: Boot, Arnoud
name: Bootwalla, Moiz S
name: Borg, Ake
name: Borkhardt, Arndt
name: Boroevich, Keith A
name: Borozan, Ivan
name: Borst, Christoph
name: Bosenberg, Marcus
name: Bosio, Mattia
name: Boultwood, Jacqueline
name: Bourque, Guillaume
name: Bova, G Steven
name: Bowen, David T
name: Bowlby, Reanne
name: Bowtell, David DL
name: Boyault, Sandrine
name: Boyce, Rich
name: Boyd, Jeffrey
name: Brazma, Alvis
name: Brennan, Paul
name: Brewer, Daniel S
name: Brinkman, Arie B
name: Broaddus, Russell R
name: Brock, Jane E
name: Brock, Malcolm
name: Broeks, Annegien
name: Brooks, Angela N
name: Brooks, Denise
name: Brors, Benedikt
name: Brunak, Søren
name: Bruxner, Timothy JC
name: Bruzos, Alicia L
name: Buchanan, Alex
name: Buchhalter, Ivo
name: Buchholz, Christiane
name: Bullman, Susan
name: Burke, Hazel
name: Burkhardt, Birgit
name: Burns, Kathleen H
name: Busanovich, John
name: Bustamante, Carlos D
name: Butler, Adam P
name: Butte, Atul J
name: Byrne, Niall J
name: Børresen-Dale, Anne-Lise
name: Caesar-Johnson, Samantha J
name: Cafferkey, Andy
name: Cahill, Declan
name: Calabrese, Claudia
name: Caldas, Carlos
name: Calvo, Fabien
name: Camacho, Niedzica
name: Campbell, Peter J
name: Campo, Elias
name: Cantù, Cinzia
name: Cao, Shaolong
name: Carey, Thomas E
name: Carlevaro-Fita, Joana
name: Carlsen, Rebecca
name: Cataldo, Ivana
name: Cazzola, Mario
name: Cebon, Jonathan
name: Cerfolio, Robert
name: Chadwick, Dianne E
name: Chakravarty, Dimple
name: Chalmers, Don
name: Chan, Calvin Wing Yiu
name: Chan, Kin
name: Chan-Seng-Yue, Michelle
name: Chandan, Vishal S
name: Chang, David K
name: Chanock, Stephen J
name: Chantrill, Lorraine A
name: Chateigner, Aurélien
name: Chatterjee, Nilanjan
name: Chayama, Kazuaki
name: Chen, Hsiao-Wei
name: Chen, Jieming
name: Chen, Ken
name: Chen, Yiwen
name: Chen, Zhaohong
name: Cherniack, Andrew D
name: Chien, Jeremy
name: Chiew, Yoke-Eng
name: Chin, Suet-Feung
name: Cho, Juok
name: Cho, Sunghoon
name: Choi, Jung Kyoon
name: Choi, Wan
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name: Chong, Zechen
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name: Chou, Angela
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name: Christie, Elizabeth L
name: Chuah, Eric
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name: Cibulskis, Kristian
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name: Demircioğlu, Deniz
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Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Structural Biology & Biophysics
subject: Structural Biology &amp; Biophysics
classificationCode: Ecology,Evolution & Ethology
subject: Ecology,Evolution &amp; Ethology
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology

description: 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.