Association between Prostinogen (KLK15) Genetic Variants and Prostate Cancer Risk and Aggressiveness in Australia and a Meta-Analysis of GWAS Data

BackgroundKallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease. ObjectivesWe performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. Methods and Data SourcesTwelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study. ResultsTwo KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (pKLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77–0.93; p = 2.7×10−4). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells. ConclusionsOur findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

背景：激肽释放酶15（KLK15）/前列腺前激肽原是前列腺癌易感性的潜在候选标志物。已有研究报道前列腺癌组织中KLK15表达升高，且该基因被认为是该病预后不良的标志物。
研究目的：本研究通过对标签单核苷酸多态性（tagSNPs）以及经大规模生物信息学分析鉴定的潜在功能性单核苷酸多态性（SNP）进行基因分型，全面分析KLK15基因变异与前列腺癌发病风险及侵袭性的关联。
方法与数据来源：本研究基于连锁不平衡（Linkage Disequilibrium, LD）模式筛选出22个单核苷酸多态性位点，其中12个在澳大利亚队列中开展基因分型分析，该队列包含1011例经组织学确诊的前列腺癌患者及1405例种族匹配的健康对照。本研究从两项已发表的全基因组关联研究（Genome-Wide Association Study, GWAS）中获取数据进行验证：分别为癌症易感性遗传标志物（Cancer Genetic Markers of Susceptibility, CGEMS）项目及英国GWAS研究。
研究结果：在澳大利亚病例对照队列中，2个KLK15基因单核苷酸多态性位点rs2659053与rs3745522表现出与前列腺癌发病风险的关联证据（p<0.05）。此外，KLK15基因位点rs2659056被发现与前列腺癌侵袭性相关，并在包含英国、澳大利亚及美国CGEMS数据集共5051例患者的验证队列中验证出关联信号。将三项研究的数据合并分析后，该位点与格里森评分（Gleason score）呈现极显著关联，比值比（Odds Ratio, OR）为0.85（95%置信区间（Confidence Interval, CI）=0.77~0.93；p=2.7×10^-4）。生物信息学预测显示，rs2659056位点可改变视黄酸相关孤儿受体α（RORalpha）转录因子的结合活性；RORalpha可调控细胞生长与分化过程，且被证实可影响前列腺癌细胞的侵袭转移行为。
结论：本研究结果表明，在欧洲血统男性群体中，KLK15基因遗传变异参与前列腺癌的发病过程，但仍需开展超大样本量的后续研究以验证其效应量大小。