前列腺癌 (PCa) 检测和治疗的最新进展降低了这种常见癌症的发病率和死亡率。尽管取得了这些进步，PCa 仍然是美国男性癌症死亡的第二大原因。需要进一步了解致命性 PCa 的遗传基础，以推动风险检测和预防并最终降低死亡率。因此，我们着手鉴定与致命性前列腺癌 (LPCa) 病例相关的种系变异。采用两阶段研究设计，我们比较了 550 名 LPCa 患者与 488 名健康男性对照的全外显子组测序数据。根据医疗记录审查，男性被归类为患有 LPCa。使用基于基因和基因集的罕见截短变异关联测试来鉴定候选基因。通过 Firth 惩罚逻辑回归进行病例对照负担测试，并通过单侧中 p Fisher 精确检验进行病例-gnomAD 等位基因负担测试。来自这些测试的每个基因的 p 值被组合成用于候选基因选择的综合 p 值。在随后的验证阶段，使用 UK Biobank 和 Firth 的惩罚逻辑回归对每个祖先进行基因评估，并通过荟萃分析相结合。基于基因的罕见变异关联测试确定了 12 个名义上与 LPCa 相关的基因。稀有变异关联测试发现，LPCa 患者中的基因组截断种系突变的负担显着高于对照组。结合基因和基因组测试结果，选择四个名义上显着的基因（PPP1R3A、TG、PPFIBP2 和 BTN3A3）作为候选基因。随后使用英国生物银行进行的验证发现 PPP1R3A 与 LPCa 风险显着相关（比值比 2.34，CI 1.20-4.59）。具体来说，pGln662ArgfsTer7 被确定为我们数据集中 LPCa 患者中 PPP1R3A 的主要变异。个体基因和基因集分析均确定了与 LPCa 相关的候选者。 PPP1R3A 和 LPCa 风险的新颖关联值得进一步研究。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Recent advances in the detection and treatment of prostate cancer (PCa) have reduced morbidity and mortality from this common cancer. Despite these improvements, PCa remains the second leading cause of cancer death in men in the United States. Further understanding of the genetic underpinnings of lethal PCa is required to drive risk detection and prevention and ultimately reduce mortality. We therefore set out to identify germline variants associated with cases of lethal prostate cancer (LPCa).Using a two-stage study design, we compared whole-exome sequencing data of 550 LPCa patients to 488 healthy male controls. Men were classified as having LPCa based on medical record review. Candidate genes were identified using gene- and gene-set-based rare truncating variant association tests. Case-control burden testing through Firth's penalized logistic regression and case-gnomAD allelic burden testing through a one-sided mid-p Fisher's exact test were conducted. Each gene's p-values from these tests were combined into an omnibus p-value for candidate gene selection. In the subsequent validation stage, genes were assessed using the UK Biobank and Firth's penalized logistic regression for each ancestry, combined through meta-analysis.Gene-based rare variant association tests identified 12 genes nominally associated with LPCa. Rare-variant association tests identified a gene set with a significantly higher burden of truncating germline mutations in LPCa patients than controls. Combining gene- and gene-set test results, four nominally significant genes (PPP1R3A, TG, PPFIBP2, and BTN3A3) were selected as candidates. Subsequent validation using the UK Biobank found that PPP1R3A was significantly associated with LPCa risk (odds ratio 2.34, CI 1.20-4.59). Specifically, pGln662ArgfsTer7 was identified as the predominant variant in PPP1R3A among LPCa patients in our dataset.Both individual gene and gene-set analyses identified candidates associated with LPCa. The novel association of PPP1R3A and LPCa risk merits further investigation.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.