使用基因和基因集关联检测识别致死性前列腺癌相关基因
Using gene and gene-set association tests to identify lethal prostate cancer genes
影响因子:5.80000
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
摘要
近年来，前列腺癌（PCa）的检测和治疗取得了显著进展，降低了该常见癌症的发病率和死亡率。尽管如此，PCa仍是美国男性第二大癌症死亡原因。深入了解致死性前列腺癌的遗传基础，对于风险检测与预防、最终降低死亡率具有重要意义。我们采用两阶段研究设计，将550例致死性前列腺癌（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。通过基因和基因集的稀有截断变异关联检测，筛选候选基因。采用Firth惩罚逻辑回归进行病例对照负荷检验，以及单向中p Fisher精确检验进行病例-gnomAD等位基因负荷检验。各基因的p值被整合为一个总的p值，用于候选基因的筛选。在后续验证阶段，利用UK Biobank数据和Firth逻辑回归分别对不同血统进行评估，并通过Meta分析合并结果。基于基因的稀有变异关联检测识别出12个与LPCa初步相关的基因。稀有变异关联检测还发现，某一基因集中的截断突变负荷显著高于对照。结合基因和基因集检验结果，筛选出4个边缘显著的候选基因（PPP1R3A、TG、PPFIBP2和BTN3A3），其中PPP1R3A在UK Biobank中的风险关联显著（OR：2.34，CI：1.20-4.59）。特别是，在我们的数据集中，PPP1R3A的主要突变为pGln662ArgfsTer7。个别基因和基因集分析均发现与LPCa相关的候选基因，PPP1R3A与LPCa风险的新的关联值得进一步研究。
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.