Toll-like receptor signaling pathway variants and prostate cancer mortality

An understanding of factors associated with prostate cancer (PCa) mortality is increasingly important given the biological heterogeneity of disease. Previous studies have shown that genetic variation in the Toll-like receptor (TLR) signaling pathway is associated with PCa incidence, but any role in progression and mortality is unclear. Among 1,252 PCa cases from the Cancer Prostate in Sweden study, we conducted time-to-event analyses of PCa mortality for 99 individual tagging SNPs and haploytpes from 20 genes in the TLR pathway. Cox proportional hazards models were used to estimate hazard ratios (HR) and 99% confidence intervals (99% CI). Global P values were estimated from a likelihood ratio test. During a median follow-up of 5.1 years, 191 PCa deaths occurred. Controlling for age and geographic location, two polymorphisms were statistically significantly associated with PCa mortality (P < 0.01). Compared with homozygous wild-type carriers of the TLR-9 polymorphism (rs187084), the HR (99% CI) was 1.57 (1.02, 2.41) for heterozygotes and 1.02 (0.57, 1.84) for rare homozygotes (P = 0.009). For a MIC-1 SNP (rs1227732), the HR comparing carriers of at least one copy of the minor allele to wild-type homozygotes was 0.54 (99% CI: 0.34, 0.87). Only the MIC-1 SNP remained significant after additional adjustment for treatment. No significant associations were observed for common haplotypes and PCa mortality. This study highlights the importance of studies of PCa mortality because risk factors for incidence and mortality may differ.