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Pathway and network analysis of more than 2500 whole cancer genomes

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posted on 2023-01-03, 10:46 authored by Matthew A Reyna, David Haan, Marta Paczkowska, Lieven PC Verbeke, Miguel Vazquez, Abdullah Kahraman, Sergio Pulido-Tamayo, Jonathan Barenboim, Lina Wadi, Priyanka Dhingra, Raunak Shrestha, Gad Getz, Michael S Lawrence, Jakob Skou Pedersen, Mark A Rubin, David A Wheeler, Søren Brunak, Jose MG Izarzugaza, Ekta Khurana, Kathleen Marchal, Christian von Mering, S Cenk Sahinalp, Alfonso Valencia, Federico Abascal, Samirkumar B Amin, Gary D Bader, Pratiti Bandopadhayay, Rameen Beroukhim, Johanna Bertl, Keith A Boroevich, John Busanovich, Peter J Campbell, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, Ken Chen, Jung Kyoon Choi, Jordi Deu-Pons, Klev Diamanti, Lars Feuerbach, J Lynn Fink, Nuno A Fonseca, Joan Frigola, Carlo Gambacorti-Passerini, Dale W Garsed, Mark Gerstein, Qianyun Guo, Ivo G Gut, Mark P Hamilton, Nicholas J Haradhvala, Arif O Harmanci, Mohamed Helmy, Carl Herrmann, Julian M Hess, Asger Hobolth, Ermin Hodzic, Chen Hong, Henrik Hornshøj, Keren Isaev, Rory Johnson, Todd A Johnson, Malene Juul, Randi Istrup Juul, Andre Kahles, Manolis Kellis, Jaegil Kim, Jong K Kim, Youngwook Kim, Jan Komorowski, Jan O Korbel, Sushant Kumar, Andrés Lanzós, Erik Larsson, Donghoon Lee, Kjong-Van Lehmann, Shantao Li, Xiaotong Li, Ziao Lin, Eric Minwei Liu, Lucas Lochovsky, Shaoke Lou, Tobias Madsen, Iñigo Martincorena, Alexander Martinez-Fundichely, Yosef E Maruvka, Patrick D McGillivray, William Meyerson, Ferran Muiños, Loris Mularoni, Hidewaki Nakagawa, Morten Muhlig Nielsen, Keunchil Park, Kiejung Park, Tirso Pons, Iker Reyes-Salazar, Esther Rheinbay, Carlota Rubio-Perez, Gordon Saksena, Leonidas Salichos, Chris Sander, Steven E Schumacher, Mark Shackleton, Ofer Shapira, Ciyue Shen, Shimin Shuai, Nikos Sidiropoulos, Lina Sieverling, Nasa Sinnott-Armstrong, Lincoln D Stein, David Tamborero, Grace Tiao, Tatsuhiko Tsunoda, Husen M Umer, Liis Uusküla-Reimand, Claes Wadelius, Jiayin Wang, Jonathan Warrell, Sebastian M Waszak, Joachim Weischenfeldt, Guanming Wu, Jun Yu, Jing Zhang, Xuanping Zhang, Yan Zhang, Zhongming Zhao, Lihua Zou, Jüri Reimand, Joshua M Stuart, Benjamin J Raphael, Lauri A Aaltonen, 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, 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, Adrian Baez-Ortega, Matthew H Bailey, Peter J Bailey, Miruna Balasundaram, Saianand Balu, Rosamonde E Banks, Stefano Barbi, Andrew P Barbour, 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, Mario Berrios, Samantha Bersani, Miguel Betancourt, Vinayak Bhandari, 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, Ivan Borozan, Christoph Borst, Marcus Bosenberg, Mattia Bosio, Jacqueline Boultwood, Guillaume Bourque, Paul C Boutros, 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, Robert G Bristow, Russell R Broaddus, Jane E Brock, Malcolm Brock, Annegien Broeks, Angela N Brooks, Denise Brooks, Benedikt Brors, Timothy JC Bruxner, Alicia L Bruzos, Alex Buchanan, Ivo Buchhalter, Christiane Buchholz, Susan Bullman, Hazel Burke, Birgit Burkhardt, Kathleen H Burns, 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, Elias Campo, Cinzia Cantù, Shaolong Cao, Thomas E Carey, Rebecca Carlsen, Ivana Cataldo, Mario Cazzola, Jonathan Cebon, Robert Cerfolio, Dianne E Chadwick, Don Chalmers, 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, Yiwen Chen, Zhaohong Chen, Andrew D Cherniack, Jeremy Chien, Yoke-Eng Chiew, Suet-Feung Chin, Juok Cho, Sunghoon Cho, 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, Noreen Dhalla, Neesha C Dhani, Rajiv Dhir, Anthony DiBiase, 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, Matthew A Field, 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, Christopher S Foster, Natalie S Fox, Michael Fraser, Scott Frazer, Milana Frenkel-Morgenstern, William Friedman, 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, Jianjiong Gao, Shengjie Gao, Levi Garraway, Øystein Garred, Erik Garrison, Nils Gehlenborg, Josep LL Gelpi, Joshy George, Daniela S Gerhard, Clarissa Gerhauser, Jeffrey E Gershenwald, Moritz Gerstung, 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, Manaswi Gupta, Shailja Gupta, Marta Gut, Jonathan Göke, Gavin Ha, Andrea Haake, Siegfried Haas, Kerstin Haase, James E Haber, Nina Habermann, Faraz Hach, Syed Haider, Natsuko Hama, Freddie C Hamdy
The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Funding

Crick (Grant ID: 10202, Grant title: Van Loo FC001202)

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