Effect of variants in the KLK3 gene on prostate cancer survival and time to metastases in a large biobank prostate cancer dataset.

Abstract

219 Background: Prostate Specific Antigen (PSA), a serine protease, is the most widely used clinical biomarker to detect prostate cancer. It is a product of the KLK3 gene. Several SNPs in KLK3 gene have previously been implicated in prostate cancer aggressiveness and PSA levels, however, the effect of KLK3 SNPs on survival and metastatic disease is not clear. We surveyed common and rare variants within 10-Kb of the KLK3 gene to estimate their effect on prostate cancer survival and time to metastasis in a large biobank data set. Methods: We analyzed a cohort of 5,287 men who developed prostate cancer after enrollment in the Million Veterans Program (MVP), 619 of whom developed metastatic disease. We analyzed 1,583 imputed SNPs (Info-R2 > 0.3) that occurred within 10-Kb of the KLK3 gene, regardless of minor allele frequency. We conducted two separate analyses, the first concerned survival times of prostate cancer specific mortality and the second analysis concerned time to metastatic disease using the Survival R package. For each analysis, variants were collectively assessed for an effect on survival using SKAT-O (metaSeq R package). We also performed a logistic regression to test each SNP for association with Gleason score 8-10 at diagnosis. Results: We identified seven rare SNPs that significantly affected prostate cancer survival (Bonferroni corrected p<3.16e-5) within 10-Kb of KLK3, 3 of which occurred within the gene boundaries (SKAT-O p=1e-4). We also identified 11 other SNPs that significantly affected time to metastasis (SKAT-O p=7e-3). The logistic regression of each SNP on Gleason score 8-10 at diagnosis identified 20 significant SNPs. The SNPs emerging from these analyses were all rare (minor allele frequency < 1e-4), and no SNPs were in linkage disequilibrium with each other, indicating that they comprise independent signals. Conclusions: Understanding the mechanism and role of rare SNPs in the KLK3 gene in prostate cancer detection has important clinical implications, especially in an era when patients’ genetics is being used to inform PSA screening. These finding may identify patients who should undergo prostate biopsy at lower PSA thresholds and/or for whom PSA biochemical recurrence is a less reliable predictor of disease progression. Ongoing prospective and retrospective analyses of Veterans with these variants both prior to and absent any prostate cancer diagnoses and progression.