Background: Genome-wide association studies and further replication studies have successfully identified over 40 prostate cancer risk single nucleotide polymorphisms (SNPs) which account for more than 25% of the familial risk of disease. However, the evidence linking these risk SNPs to prostate cancer progression is sparse. We aimed to examine whether 45 established prostate cancer risk variants were also associated with progression to prostate cancer specific mortality in 7180 men with prostate cancer who were part of the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium (BPC3). With a median follow-up time of 7.8 years, and 726 prostate cancer specific deaths, our study will be the largest and most comprehensive study to date.
Methods: The BPC3 is a collaboration of 8 well-established cohort studies with available DNA samples. Prostate cancer cases were followed for overall mortality and prostate cancer specific deaths. We identified 53 confirmed risk SNPs from the literature that had been previously genotyped in the BPC3 using the TaqMan assay. After we excluded 8 SNPs that had a pairwise r2 of >0.2 with another SNP, 45 SNPs remained (prioritizing the SNP with the lower p-value from the literature). We used Cox proportional hazards regression to assess the association of each of the risk SNPs with time to prostate cancer specific mortality. We also constructed a genetic score by summing the number of risk alleles over the 45 SNPs for each individual. Finally, we used a Cox regression kernel-machine model with a linear kernel function to test the joint multi-marker association across the 45 SNPs.
Results: The majority of the risk SNPs for prostate cancer incidence were not significantly associated with prostate cancer mortality. Four of the risk SNPs were nominally significant (p<0.05) with lethal prostate cancer, but did not remain significant after adjustment for multiple testing (rs7629490: HR(95% CI): 0.89(0.80-0.99); rs10486567: 0.84(0.74-0.94); rs6465657: 0.89(0.80-0.99); rs7127900: 0.88(0.77-0.99). The effect estimates for these SNPs were in the opposite direction than for prostate cancer incidence. The genetic score analysis also indicated that those with the most risk alleles had a decreased rate of prostate cancer mortality (quintile 5 vs. quintile 1: HR=0.70; 95% CI: 0.55-0.90; p-trend=0.04). The multi-marker kernel machine test did not yield a significant association across the SNPs (p=0.12).
Conclusions: We did not find a consistent association among the 45 known prostate cancer risk variants and progression to prostate cancer mortality. Our findings are consistent with the growing evidence that risk factors for prostate cancer progression are different than those for incident prostate cancer. Future studies are warranted to search for variants specifically associated with lethal prostate cancer outcomes.
Citation Format: Irene M. Shui, Sara Lindstrom, Travis Gerke, Edward Giovannucci, Peter Kraft for the BPC3. Prostate cancer risk variants and disease progression in the NCI Breast and Prostate Cancer Cohort Consortium. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 76.