s41467-019-14052-x.pdf (1.69 MB)
Divergent mutational processes distinguish hypoxic and normoxic tumours
journal contribution
posted on 2023-01-03, 11:08 authored by 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, Fatima Al-Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B Alexandrov, Adrian Ally, Kathryn Alsop, Eva G Alvarez, Fernanda Amary, Samirkumar B Amin, Brice Aminou, Ole Ammerpohl, Matthew J Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparicio, Elizabeth L Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun-ichi Ariizumi, Joshua Armenia, Laurent Arnould, Sylvia Asa, Yassen Assenov, Gurnit Atwal, Sietse Aukema, J Todd Auman, Miriam RR 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 Barnholtz-Sloan, Hugh Barr, Elisabet Barrera, John Bartlett, Javier Bartolome, Claudio Bassi, Oliver F Bathe, Daniel Baumhoer, Prashant Bavi, Stephen B Baylin, Wojciech Bazant, Duncan Beardsmore, Timothy A Beck, Sam Behjati, Andreas Behren, Beifang Niu, Cindy Bell, Sergi Beltran, Christopher Benz, Andrew Berchuck, Anke K Bergmann, Erik N Bergstrom, Benjamin P Berman, Daniel M Berney, Stephan H Bernhart, Rameen Beroukhim, Mario Berrios, Samantha Bersani, Johanna Bertl, Miguel Betancourt, Shriram G Bhosle, Andrew V Biankin, Matthias Bieg, Darell Bigner, Hans Binder, Ewan Birney, Michael Birrer, Nidhan K Biswas, Bodil Bjerkehagen, Tom Bodenheimer, Lori Boice, Giada Bonizzato, Johann S De Bono, Arnoud Boot, Moiz S Bootwalla, Ake Borg, Arndt Borkhardt, Keith A Boroevich, Ivan Borozan, Christoph Borst, Marcus Bosenberg, Mattia Bosio, Jacqueline Boultwood, Guillaume Bourque, G Steven Bova, David T Bowen, Reanne Bowlby, David DL Bowtell, Sandrine Boyault, Rich Boyce, Jeffrey Boyd, Alvis Brazma, Paul Brennan, Daniel S Brewer, Arie B Brinkman, Russell R Broaddus, Jane E Brock, Malcolm Brock, Annegien Broeks, Angela N Brooks, Denise Brooks, Benedikt Brors, Søren Brunak, Timothy JC Bruxner, Alicia L Bruzos, Alex Buchanan, Ivo Buchhalter, Christiane Buchholz, Susan Bullman, Hazel Burke, Birgit Burkhardt, Kathleen H Burns, John Busanovich, Carlos D Bustamante, Adam P Butler, Atul J Butte, Niall J Byrne, Anne-Lise Børresen-Dale, Samantha J Caesar-Johnson, Andy Cafferkey, Declan Cahill, Claudia Calabrese, Carlos Caldas, Fabien Calvo, Niedzica Camacho, Peter J Campbell, Elias Campo, Cinzia Cantù, Shaolong Cao, Thomas E Carey, Joana Carlevaro-Fita, Rebecca Carlsen, Ivana Cataldo, Mario Cazzola, Jonathan Cebon, Robert Cerfolio, Dianne E Chadwick, Dimple Chakravarty, Don Chalmers, Calvin Wing Yiu Chan, Kin Chan, Michelle Chan-Seng-Yue, Vishal S Chandan, David K Chang, Stephen J Chanock, Lorraine A Chantrill, Aurélien Chateigner, Nilanjan Chatterjee, Kazuaki Chayama, Hsiao-Wei Chen, Jieming Chen, Ken Chen, Yiwen Chen, Zhaohong Chen, Andrew D Cherniack, Jeremy Chien, Yoke-Eng Chiew, Suet-Feung Chin, Juok Cho, Sunghoon Cho, Jung Kyoon Choi, Wan Choi, Christine Chomienne, Zechen Chong, Su Pin Choo, Angela Chou, Angelika N Christ, Elizabeth L Christie, Eric Chuah, Carrie Cibulskis, Kristian Cibulskis, Sara Cingarlini, Peter Clapham, Alexander Claviez, Sean Cleary, Nicole Cloonan, Marek Cmero, Colin C Collins, Ashton A Connor, Susanna L Cooke, Colin S Cooper, Leslie Cope, Vincenzo Corbo, Matthew G Cordes, Stephen M Cordner, Isidro Cortés-Ciriano, Kyle Covington, Prue A Cowin, Brian Craft, David Craft, Chad J Creighton, Yupeng Cun, Erin Curley, Ioana Cutcutache, Karolina Czajka, Bogdan Czerniak, Rebecca A Dagg, Ludmila Danilova, Maria Vittoria Davi, Natalie R Davidson, Helen Davies, Ian J Davis, Brandi N Davis-Dusenbery, Kevin J Dawson, Francisco M De La Vega, Ricardo De Paoli-Iseppi, Timothy Defreitas, Angelo P Dei Tos, Olivier Delaneau, John A Demchok, Jonas Demeulemeester, German M Demidov, Deniz Demircioğlu, Nening M Dennis, Robert E Denroche, Stefan C Dentro, Nikita Desai, Vikram Deshpande, Amit G Deshwar, Christine Desmedt, Jordi Deu-Pons, Noreen Dhalla, Neesha C Dhani, Priyanka Dhingra, Rajiv Dhir, Anthony DiBiase, Klev Diamanti, Li Ding, Shuai Ding, Huy Q Dinh, Luc Dirix, HarshaVardhan Doddapaneni, Nilgun Donmez, Michelle T Dow, Ronny Drapkin, Oliver Drechsel, Ruben M Drews, Serge Serge, Tim Dudderidge, Ana Dueso-Barroso, Andrew J Dunford, Michael Dunn, Lewis Jonathan Dursi, Fraser R Duthie, Ken Dutton-Regester, Jenna Eagles, Douglas F Easton, Stuart Edmonds, Paul A Edwards, Sandra E Edwards, Rosalind A Eeles, Anna Ehinger, Juergen Eils, Roland Eils, Adel El-Naggar, Matthew Eldridge, Kyle Ellrott, Serap Erkek, Georgia Escaramis, Shadrielle MG Espiritu, Xavier Estivill, Dariush Etemadmoghadam, Jorunn E Eyfjord, Bishoy M Faltas, Daiming Fan, Yu Fan, William C Faquin, Claudiu Farcas, Matteo Fassan, Aquila Fatima, Francesco Favero, Nodirjon Fayzullaev, Ina Felau, Sian Fereday, Martin L Ferguson, Vincent Ferretti, Lars Feuerbach, Matthew A Field, J Lynn Fink, Gaetano Finocchiaro, Cyril Fisher, Matthew W Fittall, Anna Fitzgerald, Rebecca C Fitzgerald, Adrienne M Flanagan, Neil E Fleshner, Paul Flicek, John A Foekens, Kwun M Fong, Nuno A Fonseca, Christopher S Foster, Natalie S Fox, Michael Fraser, Scott Frazer, Milana Frenkel-Morgenstern, William Friedman, Joan Frigola, Catrina C Fronick, Akihiro Fujimoto, Masashi Fujita, Masashi Fukayama, Lucinda A Fulton, Robert S Fulton, Mayuko Furuta, P Andrew Futreal, Anja Füllgrabe, Stacey B Gabriel, Steven Gallinger, Carlo Gambacorti-Passerini, Jianjiong Gao, Shengjie Gao, Levi Garraway, Øystein Garred, Erik Garrison, Dale W Garsed, Nils Gehlenborg, Josep LL Gelpi, Joshy George, Daniela S Gerhard, Clarissa Gerhauser, Jeffrey E Gershenwald, Mark Gerstein, Moritz Gerstung, Gad Getz, Mohammed Ghori, Ronald Ghossein, Nasra H Giama, Richard A Gibbs, Bob Gibson, Anthony J Gill, Pelvender Gill, Dilip D Giri, Dominik Glodzik, Vincent J Gnanapragasam, Maria Elisabeth Goebler, Mary J Goldman, Carmen Gomez, Santiago Gonzalez, Abel Gonzalez-Perez, Dmitry A Gordenin, James Gossage, Kunihito Gotoh, Ramaswamy Govindan, Dorthe Grabau, Janet S Graham, Robert C Grant, Anthony R Green, Eric Green, Liliana Greger, Nicola Grehan, Sonia Grimaldi, Sean M Grimmond, Robert L Grossman, Adam Grundhoff, Gunes Gundem, Qianyun Guo, Manaswi Gupta, Shailja Gupta, Ivo G Gut, Marta Gut, Jonathan Göke, Gavin Ha, Andrea Haake, David Haan, Siegfried Haas, Kerstin Haase, James E Haber, Nina Habermann, Faraz Hach, Syed Haider, Natsuko Hama, Freddie C Hamdy, Anne Hamilton, Mark P Hamilton, Leng Han, George B Hanna, Martin Hansmann, Nicholas J Haradhvala, Olivier Harismendy, Ivon Harliwong, Arif O Harmanci, Eoghan Harrington, Takanori Hasegawa, David Haussler, Steve Hawkins, Shinya Hayami, Shuto Hayashi, D Neil Hayes, Stephen J Hayes, Nicholas K Hayward, Steven Hazell, Yao He, Allison P Heath, Simon C Heath, David Hedley, Apurva M Hegde, David I Heiman, Michael C Heinold, Zachary Heins, Lawrence E Heisler, Eva Hellstrom-Lindberg, Mohamed Helmy, Seong Gu Heo, Austin J Hepperla, José María Heredia-Genestar, Carl Herrmann, Peter Hersey, Julian M Hess, Holmfridur Hilmarsdottir, Jonathan Hinton, Satoshi Hirano, Nobuyoshi Hiraoka, Katherine A Hoadley, Asger Hobolth, Ermin Hodzic, Jessica I Hoell, Steve Hoffmann, Oliver Hofmann, Andrea Holbrook, Aliaksei Z Holik, Michael A Hollingsworth, Oliver Holmes, Robert A Holt, Chen Hong, Eun Pyo Hong, Jongwhi H Hong, Gerrit K Hooijer, Henrik Hornshøj, Fumie Hosoda, Yong Hou, Volker Hovestadt, William Howat, Alan P Hoyle, Ralph H Hruban, Jianhong Hu, Taobo Hu, Xing Hua, Kuan-lin Huang, Mei Huang, Mi Ni Huang, Vincent Huang, Yi Huang, Wolfgang Huber, Thomas J Hudson, Michael Hummel, Jillian A Hung, David Huntsman, Ted R Hupp, Jason Huse, Matthew R Huska, Barbara Hutter, Carolyn M Hutter, Daniel Hübschmann, Christine A Iacobuzio-Donahue, Charles David Imbusch, Marcin Imielinski, Seiya Imoto, William B Isaacs, Keren Isaev, Shumpei Ishikawa, Murat Iskar, SM Ashiqul Islam, Michael Ittmann, Sinisa Ivkovic, Jose MG Izarzugaza, Jocelyne Jacquemier, Valerie Jakrot, Nigel B Jamieson, Gun Ho Jang, Se Jin JangMany 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.
