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

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao Ou Shu, Jirong Long, Qiuyin CaiXingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran 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, Li Li, Franzel van Duijnhoven, Edith Feskens

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35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)89-99
Number of pages11
JournalNature Genetics
Volume55
Issue number1
Early online dateDec 2022
DOIs
Publication statusPublished - Jan 2023

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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

    Fernandez-Rozadilla, C. (Creator), Timofeeva, M. (Creator), Chen, Z. (Creator), Law, P. (Creator), Thomas, M. (Creator), Schmit, S. (Creator), Díez-Obrero, V. (Creator), Hsu, L. (Creator), Fernandez-Tajes, J. (Creator), Palles, C. (Creator), Sherwood, K. (Creator), Briggs, S. (Creator), Svinti, V. (Creator), Donnelly, K. (Creator), Farrington, S. (Creator), Blackmur, J. (Creator), Vaughan-Shaw, P. (Creator), Shu, X. O. (Creator), Long, J. (Creator), Cai, Q. (Creator), Guo, X. (Creator), Lu, Y. (Creator), Broderick, P. (Creator), Studd, J. (Creator), Huyghe, J. (Creator), Harrison, T. (Creator), Conti, D. (Creator), Dampier, C. (Creator), Devall, M. (Creator), Schumacher, F. (Creator), Melas, M. (Creator), Rennert, G. (Creator), Obón-Santacana, M. (Creator), Martín-Sánchez, V. (Creator), Moratalla-Navarro, F. (Creator), Oh, J. H. (Creator), Kim, J. (Creator), Jee, S. H. (Creator), Jung, K. J. (Creator), Kweon, S. S. (Creator), Shin, M. H. (Creator), Shin, A. (Creator), Ahn, Y. O. (Creator), Kim, D. H. (Creator), Oze, I. (Creator), Wen, W. (Creator), Matsuo, K. (Creator), Li, L. (Creator), van Duijnhoven, F. (Creator) & Feskens, E. (Creator), Wageningen University, 1 Aug 2022

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