Background:

Several lines of evidence support the roles of inflammation and infection in prostate cancer development and progression. Common genetic variants involved in pathways of inflammation and immune response may be important for prostate cancer. The Toll-like receptor 4 (TLR4) is a cell surface receptor that mediates immune response. TLR4 recognizes LPS (endotoxin) on gram-negative bacteria, resulting in NF-kappaB and cytokine production as well as inducing interferon expression. In vitro studies suggest that stimulation of TLR4 with LPS promotes prostate tumor growth. Yet, single nucleotide polymorphisms (SNPs) on TLR4 have been inconsistently associated with prostate cancer risk, and only one published study has looked at survival as an endpoint.

Methods:

In a large nested case control study of prostate cancer in the Physicians’ Health Study (1982-2004), 10 SNPs were selected and genotyped to capture common variation within the TLR4 gene as well as 5 kilobases up and downstream. SNPs that were not directly tagged were imputed using the observed genotypes, the HapMap CEPH data, and the MACH imputation program. Unconditional logistic regression controlling for matching factors (age at randomization, smoking status and duration of follow-up) assessed the association of these SNPs and prostate cancer risk (odds ratios (OR) and 95% confidence intervals (CI)), as well as risk defined by advanced cancer stage (T3/T4, T0-T4/M1, fatal disease) or high Gleason grade (>=7). Time to event analysis using Cox-proportional hazards regression assessed risk of progression to metastases and death among prostate cancer cases through March 2009.

Results:

The case-control analysis included 1286 prostate cancer cases and 1267 controls; there were 237 advanced stage and 560 high grade cases. An additional 45 men who were originally controls developed prostate cancer and were also included in the case-only survival analysis. During a median of 10.6 years of follow-up, 183 men died of prostate cancer or developed distant metastases. No significant associations between the TLR4 SNPs were found for total prostate cancer risk, including SNPs for which an association was reported in other published studies: rs2149356 (OR:0.89, CI: 0.66, 1.18); rs2737191 (OR: 1.01, CI:0.75, 1.37); rs10759932 (OR: 1.08, CI: 0.89, 1.3); rs11536889 (OR: 0.99, CI: 0.83, 1.19). There were no significant associations for risk of advanced stage or high grade cancers, or progression to metastases or death.

Conclusions:

Results from this prospective nested case-control study, with a large number of aggressive cancers and comprehensive SNP selection on TLR4, suggest that genetic variation across TLR4 is not associated with prostate cancer risk or progression. The results do not replicate the findings of previous studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 920.