利用基因与基因集关联检验鉴定致命前列腺癌相关基因
Using gene and gene-set association tests to identify lethal prostate cancer genes
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发表日期:2025 Jun
作者:
Bing-Jian Feng, Julie L Boyle, Jun Wei, Courtney Carroll, Nathan A Snyder, Zhuqing Shi, S Lilly Zheng, Jianfeng Xu, William B Isaacs, Kathleen A Cooney
DOI:
10.1038/s41391-024-00879-z
摘要
近年来，前列腺癌（PCa）的检测和治疗取得了进展，降低了该常见癌症的发病率和死亡率。尽管如此，前列腺癌仍然是美国男性癌症死亡的第二大原因。深入理解致命性前列腺癌的遗传基础对于风险检测、预防以及最终减少死亡具有重要意义。因此，我们旨在鉴定与致命性前列腺癌（LPCa）相关的生殖系变异。采用两阶段研究设计，将550例LPCa患者的全外显子测序数据与488名健康男性对照进行比较。通过医学记录审查，将男性归类为LPCa病例。候选基因采用基因及基因集的稀有终止突变关联检验进行鉴定。采用Firth的惩罚逻辑回归进行病例对照负担检验，以及单边中p Fisher精确检验进行病例-gnomAD等位基因负担检验。每个基因的p值结合成一个总p值，用于候选基因的筛选。在随后的验证阶段，利用UK Biobank及Firth的惩罚逻辑回归，按不同血统进行分析，并通过荟萃分析合并结果。基于稀有变异的基因关联检验发现12个基因与LPCa呈名义相关。稀有变异关联检验还发现一个基因集在LPCa患者中具有显著更高的终止突变负担。结合基因和基因集的检验结果，筛选出四个名义显著的候选基因（PPP1R3A、TG、PPFIBP2和BTN3A3）。在UK Biobank的验证中，PPP1R3A与LPCa风险显著相关（比值比2.34，95%置信区间1.20-4.59），特别是在我们数据集中，pGln662ArgfsTer7是PPP1R3A中占主导地位的变异。
Abstract
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.