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.
Nature genetics. 2024 Oct 29 [Epub]
Erna V Ivarsdottir, Julius Gudmundsson, Vinicius Tragante, Gardar Sveinbjornsson, Snaedis Kristmundsdottir, Simon N Stacey, Gisli H Halldorsson, Magnus I Magnusson, Asmundur Oddsson, G Bragi Walters, Asgeir Sigurdsson, Saedis Saevarsdottir, Doruk Beyter, Gudmar Thorleifsson, Bjarni V Halldorsson, Pall Melsted, Hreinn Stefansson, Ingileif Jonsdottir, Erik Sørensen, Ole B Pedersen, Christian Erikstrup, Martin Bøgsted, Mette Pøhl, Andreas Røder, Hein Vincent Stroomberg, Ismail Gögenur, Jens Hillingsø, Stig E Bojesen, Ulrik Lassen, Estrid Høgdall, Henrik Ullum, Søren Brunak, Sisse R Ostrowski, DBDS Genomic Consortium , Ida Elken Sonderby, Oleksandr Frei, Srdjan Djurovic, Alexandra Havdahl, Pal Moller, Mev Dominguez-Valentin, Jan Haavik, Ole A Andreassen, Eivind Hovig, Bjarni A Agnarsson, Rafn Hilmarsson, Oskar Th Johannsson, Trausti Valdimarsson, Steinn Jonsson, Pall H Moller, Jon H Olafsson, Bardur Sigurgeirsson, Jon G Jonasson, Geir Tryggvason, Hilma Holm, Patrick Sulem, Thorunn Rafnar, Daniel F Gudbjartsson, Kari Stefansson
deCODE genetics/Amgen, Reykjavik, Iceland. ., deCODE genetics/Amgen, Reykjavik, Iceland., Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark., Center for Clinical Data Science, Aalborg University and Aalborg University Hospital, Aalborg, Denmark., Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Department of Transplantation, Digestive Diseases and General Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., HU Statens Serum Institut, Copenhagen, Denmark., Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway., K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway., Center for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway., Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Department of Biomedicine, University of Bergen, Bergen, Norway., Division of Mental Health and Addiction, Centre for Precision Psychiatry, University of Oslo and Oslo University Hospital, Oslo, Norway., Department of Informatics, Centre for Bioinformatics, University of Oslo, Oslo, Norway., Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Department of General Surgery, Landspitali University Hospital, Reykjavik, Iceland., Department of Oncology, Landspitali University Hospital, Reykjavik, Iceland., The Medical Center, Glaesibae, Reykjavik, Iceland., deCODE genetics/Amgen, Reykjavik, Iceland. .