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.

在种系基因组序列中发现癌症风险变异可以揭示致癌作用。在这里，我们描述了基因负担关联分析，汇总了 22 个癌症部位的罕见错义和功能丧失变异，包括来自冰岛、挪威和英国的 130,991 例癌症病例和 733,486 例对照。我们确定了四个与癌症风险增加相关的基因;促凋亡 BIK 用于前列腺癌，自噬涉及用于结直肠癌的 ATG12、用于甲状腺癌的 TG 和用于肺癌和皮肤黑色素瘤的 CMTR2。此外，我们发现具有与癌症风险降低相关的罕见变异的基因;AURKB 适用于任何癌症，无论部位如何，PPP1R15A适用于乳腺癌，这表明抑制 PPP1R15A 可能是乳腺癌的一种预防策略。我们的研究结果确定了几种新的癌症风险基因，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。