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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 55 |
| Sider (fra-til) | 89-99 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - jan. 2023 |
Bibliografisk note
Funding Information:At the Institute of Cancer Research, this work was supported by Cancer Research UK (CRUK, grant no. C1298/A25514 to R.S.H.). Additional support was provided by the National Cancer Research Network. In Edinburgh, the work was supported by program grant funding from CRUK (grant nos. C348/A12076 to M.G.D. and C6199/A16459 to I.T.), EU European Research Council Advanced Grant EVOCAN, and the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre. C.F.R. was supported by a Marie Sklodowska-Curie Intra-European Fellowship Action (grant no. IEF-301077) for the INTERMPHEN project and received considerable help from many staff in the Department of Endoscopy at the John Radcliffe Hospital in Oxford. Support from the European Union (grant nos. FP7/207–2013 and 258236), FP7 collaborative project SYSCOL and COST Actions EuColonGene and TransColonCan are also acknowledged (grant nos. BM1206 and CA17118 to I.T.). We are grateful to many colleagues within UK clinical genetics departments (for CORGI) and to many collaborators who participated in the VICTOR, QUASAR2 and SCOT trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). IT acknowledges funding from CRUK program grant no. C6199/A27327. The work at Vanderbilt University Medical Center was supported by US National Institutes of Health (NIH; grant nos. R01CA188214, R37CA070867, UM1CA182910, R01CA124558, R01CA158473 and R01CA148667), as well as Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine (to W.Z.). Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, supported in part by the Vanderbilt-Ingram Cancer Center (grant no. P30CA068485). Statistical analyses were performed on servers maintained by the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCC), National Cancer Institute (NCI), NIH, US Department of Health and Human Services provided grant nos. U01 CA164930, U01 CA137088, R01 CA059045, R01201407 and R01CA206279. Genotyping services were provided by the Center for Inherited Disease Research (CIDR) contract no. HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center support grant no. P30 CA015704. Scientific Computing Infrastructure at the Fred Hutchinson Cancer Research Center was funded by ORIP grant no. S10OD028685 (to U.P.). The Colorectal Cancer Transdisciplinary (CORECT) study was supported by the NCI/NIH, US Department of Health and Human Services (grant nos. U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, P01 CA196569 and R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant no. T32 ES013678). The Colon Cancer Family Registry (CCFR) participant recruitment and collection of data and biospecimens used in the present study were supported by the NCI, NIH (grant no. U01 CA167551). OFCCR was supported through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant no. U01 CA074783). The content of this manuscript does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the CCFR, and the mention of trade names, commercial products or organizations does not imply endorsement by the US Government, any cancer registry or the CCFR.
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© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.