CUA 2017: Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer

Toronto, Ontario ( Prostate Cancer (PCa) is a highly heterogeneous disease, ranging from indolent to rapidly progressing life-threatening metastatic disease. There is a need for markers identifying patients at increased risk of harbouring aggressive forms of PCa. Dr. Alexandre Zlotta presented a study surveying the Kallikrein (KLK) region (KLK1-15) for single nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason score ≥8) in 1858 PCa patients. 

For the purpose of this study, patients from the Discovery (Swiss arm of the European Randomized Study of Screening for PCa, n=379); from Toronto, Canada, Princess Margaret Cancer Centre, n=540; and patients from a validation cohort (Prostate, Lung, Colorectal, and Ovarian [PLCO], n=939) were analyzed. Fine-mapping was carried out by genotyping and imputation (Discovery cohort) or provided by dbGaP (PLCO). Biochemical-free survival was evaluated in an intermediate-risk disease cohort (International Cancer Genome Consortium [ICGC]; n=130). Single- and multi-SNP association studies, as well as haplotype analyses were performed. All statistical tests were two-sided.

Five SNPs in strong linkage disequilibrium in the KLK6 region, within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified patients at increased risk of aggressive PCa in both discovery (odds ratio [OR] 3.51‒3.64; 95% confidence interval [CI] 2.01-6.36; p=1.0 x 10-5‒8.4 x 10-6) and validation (OR 1.89‒1.96; 95% CI 0.99‒3.71; p=0.04‒0.05) cohorts. 

The validation cohort revealed another important haplotype with two SNPs at the same locus (rs28665094, p=0.006 and rs268890; p=0.005) associated with aggressive PCa. The overall test of haplotype association was highly statistically significant in the discovery cohort (p=3.5 x 10-4), in the PLCO cohort (p=0.006) and when combined (p=2.3 x 10-5). These germline SNPs predicted relapse independently of standard clinical and molecular factors in the ICGC cohort (hazard ratio [HR] 3.15; 95% CI 1.57‒6.34; p=0.001).

Dr. Zlotta summarized his interesting talk by stating that this fine-mapping study has identified novel loci in the KLK6 region strongly associated with aggressive PCa and predicting biochemical relapse. After further sequencing studies are performed to help identify rare variants with major effect in this KLK6 region, these novel biomarkers could have tremendous potential use.

Presented By: Alexandre Zlotta, MD, PhD, FRCSC, Mount Sinai Hospital, Toronto, ON

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre  Twitter: @GoldbergHanan at the  72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada