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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
Edinburgh Cancer Research Centre, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Genomic Medicine Group, Instituto de Investigacion Sanitaria de Santiago, Santiago de Compostela, Spain.
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Danish Institute for Advanced Study, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, TN, Nashville, United States.
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
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2023 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 55, p. 89-99Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2023. Vol. 55, p. 89-99
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:umu:diva-202082DOI: 10.1038/s41588-022-01222-9ISI: 001001563800001PubMedID: 36539618Scopus ID: 2-s2.0-85144441436OAI: oai:DiVA.org:umu-202082DiVA, id: diva2:1723453
Funder
NIH (National Institutes of Health), R01CA124558, R01CA148667, R01CA158473, R01CA188214, R37CA070867, UM1CA182910
Note

Errata: Fernandez-Rozadilla, C., Timofeeva, M., Chen, Z. et al. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries. Nat Genet (2023). DOI: 10.1038/s41588-023-01334-w

Available from: 2023-01-03 Created: 2023-01-03 Last updated: 2025-04-24Bibliographically approved

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van Guelpen, Bethany

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