冰岛deCODE遗传公司/安进公司Kari Stefansson和Erna V. Ivarsdottir共同合作，近期取得重要工作进展。他们基于基因的罕见生殖变异负担测试鉴定出了六种癌症易感基因。相关研究成果2024年10月29日在线发表于《自然—遗传学》杂志上。

据介绍，在种系基因组序列中发现癌症风险变异可以阐明致癌作用。

研究人员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丧失变体，包括来自冰岛、挪威和英国的130991例癌症病例和733486例对照。研究人员鉴定了四个与癌症风险增加相关的基因；前列腺癌的促凋亡BIK，结直肠癌的ATG12，甲状腺癌的TG，肺癌和皮肤黑色素瘤的CMTR2参与自噬。

此外，研究人员发现了具有罕见变异的基因，这些变异与癌症风险的降低有关；AURKB用于任何癌症，无论部位如何，PPP1R15A适用于乳腺癌，表明抑制PPP1R15A可能是乳腺癌的一种预防策略。

总之，这一研究结果确定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。

附：英文原文

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

Author: Ivarsdottir, Erna V., Gudmundsson, Julius, Tragante, Vinicius, Sveinbjornsson, Gardar, Kristmundsdottir, Snaedis, Stacey, Simon N., Halldorsson, Gisli H., Magnusson, Magnus I., Oddsson, Asmundur, Walters, G. Bragi, Sigurdsson, Asgeir, Saevarsdottir, Saedis, Beyter, Doruk, Thorleifsson, Gudmar, Halldorsson, Bjarni V., Melsted, Pall, Stefansson, Hreinn, Jonsdottir, Ingileif, Srensen, Erik, Pedersen, Ole B., Erikstrup, Christian, Bgsted, Martin, Phl, Mette, Rder, Andreas, Stroomberg, Hein Vincent, Ggenur, Ismail, Hillings, Jens, Bojesen, Stig E., Lassen, Ulrik, Hgdall, Estrid, Ullum, Henrik, Brunak, Sren, Ostrowski, Sisse R., Sonderby, Ida Elken, Frei, Oleksandr, Djurovic, Srdjan, Havdahl, Alexandra, Moller, Pal, Dominguez-Valentin, Mev, Haavik, Jan, Andreassen, Ole A., Hovig, Eivind, Agnarsson, Bjarni A., Hilmarsson, Rafn, Johannsson, Oskar Th., Valdimarsson, Trausti, Jonsson, Steinn, Moller, Pall H., Olafsson, Jon H., Sigurgeirsson, Bardur, Jonasson, Jon G., Tryggvason, Geir, Holm, Hilma, Sulem, Patrick, Rafnar, Thorunn, Gudbjartsson, Daniel F., Stefansson, Kari

Issue&Volume: 2024-10-29

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.

DOI: 10.1038/s41588-024-01966-6

Source: https://www.nature.com/articles/s41588-024-01966-6