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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

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Fernandez-Rozadilla, C and Timofeeva, M and Chen, Z and Law, P and Thomas, M and Schmit, S and DA ez-Obrero, V and Hsu, L and Fernandez-Tajes, J and Palles, C and Sherwood, K and Briggs, S and Svinti, V and Donnelly, K and Farrington, S and Blackmur, J and Vaughan-Shaw, P and Shu, XO and Long, J and Cai, Q and Guo, X and Lu, Y and Broderick, P and Studd, J and Huyghe, J and Harrison, T and Conti, D and Dampier, C and Devall, M and Schumacher, F and Melas, M and Rennert, G and ObA n-Santacana, M and MartA n-SA nchez, V and Moratalla-Navarro, F and Oh, JH and Kim, J and Jee, SH and Jung, KJ and Kweon, SS and Shin, MH and Shin, A and Ahn, YO and Kim, DH and Oze, I and Wen, W and Matsuo, K and Matsuda, K and Tanikawa, C and Ren, Z and Gao, YT and Jia, WH and Hopper, J and Jenkins, M and Win, AK and Pai, R and Figueiredo, J and Haile, R and Gallinger, S and Woods, M and Newcomb, P and Duggan, D and Cheadle, J and Kaplan, R and Maughan, T and Kerr, R and Kerr, D and Kirac, I and BA hm, J and Mecklin, LP and Jousilahti, P and Knekt, P and Aaltonen, L and Rissanen, H and Pukkala, E and Eriksson, J and Cajuso, T and Hanninen, U and Kondelin, J and Palin, K and Tanskanen, T and Renkonen-Sinisalo, L and Zanke, B and Mannisto, S and Albanes, D and Weinstein, S and Ruiz-Narvaez, E and Palmer, J and Buchanan, D and Platz, E and Visvanathan, K and Ulrich, C and Siegel, E and Brezina, S and Gsur, A and Campbell, P and Chang-Claude, J and Hoffmeister, M and Brenner, H and Slattery, M and Fitzgerald, L, Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries, Nature Genetics, 55, (1) pp. 89-99. ISSN 1061-4036 (2023) [Refereed Article]


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DOI: doi:10.1038/s41588-022-01222-9

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.

Item Details

Item Type:Refereed Article
Keywords:colorectal cancer, genome-wide association study, meta-analysis, risk variants
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Gene mapping
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Fitzgerald, L (Dr Liesel FitzGerald)
ID Code:154878
Year Published:2023
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-01-17
Last Modified:2023-01-17
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