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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

2022; Nature Portfolio; Volume: 55; Issue: 1 Linguagem: Inglês

10.1038/s41588-022-01222-9

1546-1718

Ceres Fernández‐Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie L. Schmit, Virginia Díez‐Obrero, Li Hsu, Juan Fernández‐Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James P. Blackmur, P G Vaughan-Shaw, Xiao‐Ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James B. Studd, Jeroen R. Huyghe, Tabitha A. Harrison, David V. Conti, Christopher H. Dampier, Mathew Devall, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón‐Santacana, Vicente Martín, Ferrán Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun‐Seog Kweon, Min‐Ho Shin, Aesun Shin, Yoon‐Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu‐Tang Gao, Wei‐Hua Jia, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Tim Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, ­Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika A. Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen‐Sinisalo, Brent W. Zanke, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward A. Ruiz‐Narváez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin M. Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang‐Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Konstantinos K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellvı́-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana C. Stern, Bens Pardamean, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu‐Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu‐Ru Su, Robert S. Steinfelder, Temitope O. Keku, Bethany Van Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Douglas A. Corley, Paul D.P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz‐Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz‐Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Deborah A. Nickerson, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodička, Ludmila Vodičková, Veronika Vymetálková, Nickolas Papadopoulos, Chistopher Edlund, W. James Gauderman, Duncan C. Thomas, David Shibata, Amanda E. Toland, Sanford D. Markowitz, Andre Kim, Stephen J. Chanock, Fränzel van Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago‐Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross L. Prentice, Conghui Qu, Stéphane Bézieau, Catherine M. Tangen, Elaine R. Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher A. Haiman, Loı̈c Le Marchand, Anna H. Wu, Chenxu Qu, Caroline McNeil, Gerhard A. Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Τheodoratou, S. Reid, Marion Walker, Li Yin Ooi, Vı́ctor Moreno, Graham Casey, Stephen B. Gruber, Ian Tomlinson, Wei Zheng, Malcolm G. Dunlop, Richard S. Houlston, Ulrike Peters,

Colorectal Cancer Screening and Detection

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies. A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.