Introduction

Prostate Cancer (PCa) is a highly heterogeneous disease, ranging from indolent tumors to rapidly progressing life-threatening metastatic disease. There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of PCa.

Methods

We surveyed the Kallikrein (KLK) region (KLK1-15) for single nucleotide polymorphisms (SNPs) associated with aggressive PCa (defined as Gleason Score ≥8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n=379, and Toronto, Canada, Princess Margaret Cancer Centre, n=540) and a validation cohort (Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, n=939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort whereas PLCO data was provided through DbGaP. The influence of SNPs of interest on biochemical free survival was evaluated in an intermediate-risk disease patient cohort from the International Cancer Genome Consortium (ICGC; n=130) treated for localized PCa and analyzed with next generation sequencing. Single-, multi-SNP association studies, and haplotype analyses were performed. All statistical tests were two sided.

Results

Several SNPs in very strong linkage disequilibrium in the KLK6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (OR=3.51-3.64; 95%CI=2.01-6.36; p=1.0x10^-5-8.4x10^-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 2 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=3.5x10^-4), in the PLCO cohort (p=0.006) and in the three data sets combined (p=2.3x10^-5). These germline SNPs predicted relapse independently of standard clinical and molecular factors in the ICGC cohort (HR=3.15, 95%CI=1.57-6.34 p=0.001).

Conclusions

Our fine-mapping study has identified novel loci in the KLK6 region strongly associated with aggressive PCa. Additional sequencing studies might help identify rare variants with major effect in this KLK6 region.

Funding

Canadian Institutes of Health Research (CIHR; project numbers: MOP-94845 and MOP-97733)_x000D_ Ontario Institute for Cancer Research (OICR; project number: 08Nov-163)_x000D_ Prostate Cancer Canada Movember Foundation (RS2014-01)