Genetic Association of the KLK4 Locus with Risk of Prostate Cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score trendKLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

激肽释放酶相关肽酶KLK4（Kallikrein-related peptidase, KLK4）在多项研究中被证实于前列腺肿瘤内呈显著高表达，被认为是前列腺癌的潜在生物标志物（biomarker）。KLK4还可能通过参与上皮-间质转化（epithelial-mesenchymal transition）——这一与更具侵袭性表型相关的生物学过程——以及骨转移，在前列腺癌进展中发挥作用。众所周知，遗传变异可影响基因表达及/或多种蛋白质特性，因此本研究旨在探究KLK4基因内的单核苷酸多态性（single nucleotide polymorphisms, SNPs）在前列腺癌中的潜在作用。本研究针对KLK4基因座（±10 kb范围内）的61个SNPs，在约1300例前列腺癌患者与1300例男性对照中开展关联分析，以探究其与前列腺癌发病风险及/或前列腺肿瘤侵袭性（格里森评分（Gleason score）趋势）的关联；其中rs1654551可编码KLK4蛋白长异构体第22位丝氨酸向丙氨酸的错义替换，其余3个风险相关SNPs——rs1701927、rs1090649与rs806019——均位于KLK4基因下游，且彼此间存在高度连锁不平衡（linkage disequilibrium，r²≥0.98）。本研究结果为KLK4基因座的遗传变异在前列腺癌易感性中的作用提供了提示性证据。