Abstract
Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 56 |
| Sider (fra-til) | 2422–2433 |
| Antal sider | 12 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We would like to thank all study participants for their valuable contribution. We also thank all our colleagues who contributed to data and sample collecting and genotyping. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. This work was partly performed on the TSD (Services for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We thank the Norwegian Institute of Public Health for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (RCN 229624). We also thank the NORMENT Centre for providing genotype data, funded by the RCN (223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen (SKGJ). We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data funded by the ERC AdG project SELECTionPREDISPOSED, SKGJ, Trond Mohn Foundation, the RCN, the Novo Nordisk Foundation, the University of Bergen and the Western Norway Health Authorities. S.B. acknowledges the Novo Nordisk Foundation (grant nos. NNF17OC0027594 and NNF14CC0001).
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.