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, 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
{"title":"Gene-based burden tests of rare germline variants identify six cancer susceptibility genes","authors":"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, 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","doi":"10.1038/s41588-024-01966-6","DOIUrl":null,"url":null,"abstract":"<p>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 <i>BIK</i> for prostate cancer, the autophagy involved <i>ATG12</i> for colorectal cancer, <i>TG</i> for thyroid cancer and <i>CMTR2</i> for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; <i>AURKB</i> for any cancer, irrespective of site, and <i>PPP1R15A</i> 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.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41588-024-01966-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation.
Integrative genetic topics comprise, but are not limited to:
-Genes in the pathology of human disease
-Molecular analysis of simple and complex genetic traits
-Cancer genetics
-Agricultural genomics
-Developmental genetics
-Regulatory variation in gene expression
-Strategies and technologies for extracting function from genomic data
-Pharmacological genomics
-Genome evolution