最近的研究表明，在某些基因中罕见的有害变异（RDVs）是遗传癌症风险的关键决定因素。为了更全面地了解RDVs，我们对20789名参与者的全外显子组测序数据进行了迄今为止最大规模的家系变异分析，并将其分为发现组和验证组，以进行多癌症关联研究。我们确认并扩展了癌症风险与特定基因集中的家系RDVs之间已知的关联，包括DNA修复（OR=1.50；p值=8.30e-07；95% CI: 1.28-1.77）、癌症易感（OR=1.51；p值=4.58e-08；95% CI: 1.30-1.75）和体细胞癌症驱动因子（OR=1.46；p值=4.04e-06；95% CI: 1.24-1.72）。此外，这些基因集中个人的RDV负载与增加的风险、更年轻的发病年龄、肿瘤中的增加的M1巨噬细胞以及特定癌症中的增加的肿瘤突变负担有关。我们的发现可用于确定高风险个体，他们可以从增加的监测、更早的筛检和利用其肿瘤特性的治疗中受益，从而改善预后。©2023年作者。

Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28-1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30-1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24-1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis.© 2023. The Author(s).