利用基因和基因组关联测试确定致命的前列腺癌基因。

IF 5.1 2区 医学 Q1 ONCOLOGY
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
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引用次数: 0

摘要

背景:前列腺癌(PCa)检测和治疗方面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,但前列腺癌仍然是美国男性癌症死亡的第二大原因。我们需要进一步了解致命 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,我们着手确定与致死性前列腺癌(LPCa)病例相关的种系变异:我们采用两阶段研究设计,比较了 550 名致死性前列腺癌患者和 488 名健康男性对照者的全基因组测序数据。根据病历审查将男性归类为 LPCa 患者。通过基于基因和基因组的罕见截断变异关联测试确定了候选基因。通过 Firth 惩罚性逻辑回归进行病例对照负荷测试,通过单侧中位费雪精确检验进行病例等位基因负荷测试。通过这些测试得出的每个基因的 p 值被合并成一个综合 p 值,用于候选基因的筛选。在随后的验证阶段,使用英国生物库和 Firth 的惩罚性逻辑回归对每个祖先的基因进行评估,并通过荟萃分析进行合并:结果:基于基因的罕见变异关联测试确定了 12 个与 LPCa 名义上相关的基因。罕见变异关联测试确定了一个基因集,该基因集在 LPCa 患者中的截断种系突变负担明显高于对照组。结合基因和基因组测试结果,四个名义上重要的基因(PPP1R3A、TG、PPFIBP2 和 BTN3A3)被选为候选基因。随后利用英国生物库进行的验证发现,PPP1R3A 与 LPCa 风险显著相关(几率比 2.34,CI 1.20-4.59)。特别是,在我们的数据集中,pGln662ArgfsTer7 被确定为 LPCa 患者中 PPP1R3A 的主要变异:单个基因和基因组分析都发现了与LPCa相关的候选基因。PPP1R3A与LPCa风险的新关联值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Using gene and gene-set association tests to identify lethal prostate cancer genes.

Using gene and gene-set association tests to identify lethal prostate cancer genes.

Background: 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).

Methods: 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.

Results: 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.

Conclusions: Both individual gene and gene-set analyses identified candidates associated with LPCa. The novel association of PPP1R3A and LPCa risk merits further investigation.

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来源期刊
Prostate Cancer and Prostatic Diseases
Prostate Cancer and Prostatic Diseases 医学-泌尿学与肾脏学
CiteScore
10.00
自引率
6.20%
发文量
142
审稿时长
6-12 weeks
期刊介绍: Prostate Cancer and Prostatic Diseases covers all aspects of prostatic diseases, in particular prostate cancer, the subject of intensive basic and clinical research world-wide. The journal also reports on exciting new developments being made in diagnosis, surgery, radiotherapy, drug discovery and medical management. Prostate Cancer and Prostatic Diseases is of interest to surgeons, oncologists and clinicians treating patients and to those involved in research into diseases of the prostate. The journal covers the three main areas - prostate cancer, male LUTS and prostatitis. Prostate Cancer and Prostatic Diseases publishes original research articles, reviews, topical comment and critical appraisals of scientific meetings and the latest books. The journal also contains a calendar of forthcoming scientific meetings. The Editors and a distinguished Editorial Board ensure that submitted articles receive fast and efficient attention and are refereed to the highest possible scientific standard. A fast track system is available for topical articles of particular significance.
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