Journal Article

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

Tanskanen, Tomas, Schumacher, Fredrick, Markowitz, Sanford, Scacheri, Peter, Woods, Michael, Cajuso, Tatiana, van Duijnhoven, Franzel, Blackmur, James, Steinfelder, Robert, Díez-Obrero, Virginia, Qu, Chenxu, Dunlop, Malcolm, Ahn, Yoon-Ok, Hampe, Jochen, Mardis, Elaine, Kirac, Iva, Kweon, Sun-Seog, McDonnell, Kevin, Deary, Ian, Moratalla-Navarro, Ferran, Gunter, Marc, Wolk, Alicja, Kerr, David, Shu, Xiao-ou, Hunter, David, Doheny, Kimberly, Yamaji, Taiki, Hsu, Li, Knekt, Paul, Gsur, Andrea, Lin, Yi, Obón-Santacana, Mireia, FitzGerald, Liesel, Stern, Mariana, Castells, Antoni, Shin, Aesun, Melas, Marilena, Offit, Kenneth, Hampel, Heather, Thomas, Duncan, Joshi, Amit, Harris, Sarah, Sakoda, Lori, Gallinger, Steven, Haile, Robert, Southey, Melissa, Berndt, Sonja, Bézieau, Stéphane, Kaplan, Richard, Qu, Conghui, Sawada, Norie, Pardamean, Bens, Pardini, Barbara, Vodickova, Ludmila, Pukkala, Eero, Kooperberg, Charles, Le Marchand, Loic, Eriksson, Johan, Iwasaki, Motoki, Theodoratou, Evropi, Wen, Wanqing, Visvanathan, Kala, Feskens, Edith, Thomas, Sushma, Conti, David, Platz, Elizabeth, Shcherbina, Anna, Schoen, Robert, Martín

2023

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/177 / 631/208/205/2138 / 631/337/2019 / 692/699/67/1504/1885 / Agriculture / Animal Genetics and Genomics / Asian people / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell adhesion / Cell migration / Colorectal cancer / Colorectal Neoplasms - genetics / DNA methylation / East Asian People - genetics / European People - genetics / Gene expression / Gene Function / Genes / Genetic Predisposition to Disease / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Growth factors / Homeostasis / Human Genetics / Humans / Microorganisms / Mucosa / Multiomics / Polymorphism, Single Nucleotide - genetics / Risk analysis / Transcriptomes / Transcriptomics / Tumorigenesis