Gene-based burden tests of rare germline variants identify six cancer susceptibility genes

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2024-10-29 DOI:10.1038/s41588-024-01966-6
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
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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.

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基于基因的罕见种系变异负担测试确定了六种癌症易感基因
在种系基因组序列中发现癌症风险变异可揭示致癌过程。在这里,我们描述了基因负荷关联分析,汇总了22个癌症位点的罕见错义和功能缺失变异,包括来自冰岛、挪威和英国的130991例癌症病例和733486例对照。我们发现了四个与癌症风险增加有关的基因:促凋亡基因 BIK 与前列腺癌有关,自噬基因 ATG12 与结直肠癌有关,TG 与甲状腺癌有关,CMTR2 与肺癌和皮肤黑色素瘤有关。此外,我们还发现了与癌症风险降低相关的罕见变异基因:AURKB 与任何癌症(无论部位)相关,PPP1R15A 与乳腺癌相关,这表明抑制 PPP1R15A 可能是一种预防乳腺癌的策略。我们的研究结果指出了几个新的癌症风险基因,并强调自噬、细胞凋亡和细胞应激反应是开发新疗法的重点。
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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
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
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