COX2 genetic variation, NSAIDs, and advanced prostate cancer risk

Abstract

Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate cancer. Nine singlenucleotide polymorphisms (SNPs) in COX2 were genotyped among 1012 men in our case -control study of advanced prostate cancer. Gene -environment interactions between COX2 polymorphisms and NSAID use were also evaluated. Information on NSAID use was obtained by questionnaire. Three SNPs demonstrated nominally statistically significant associations with prostate cancer risk, with the most compelling polymorphism (rs2745557) associated with a lower risk of disease (odds ratio (OR) GC vs GG ¼ 0.64; 95% confidence interval (CI): 0.49 -0.84; P ¼ 0.002). We estimated through permutation analysis that a similarly strong result would occur by chance 2.7% of the time. Nonsteroidal anti-inflammatory drug use was associated with a lower risk of disease in comparison to no use (OR ¼ 0.67; 95% CI: 0.52 -0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P ¼ 0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk.

PTGS2–899G>C and prostate cancer risk: a population-based nested case–control study (ProtecT) and a systematic review with meta-analysis

“…12,25 Only one of these studies 12 contained information on the clinical characteristics of its case-control populations. Combining ProtecT data with these studies provided no evidence that rs20417 alters prostate cancer risk (Figure 1).…”

Meta-analysis of epidemiological studies demonstrates significant association of PTGS2 polymorphism rs689470 and no significant association of rs20417 with prostate cancer

“…According to the inclusion criteria defined above, we identified 12 independent studies in 8 eligible reports (Panguluri et al, 2004;Shahedi et al, 2006;Cheng et al, 2007;Danforth et al, 2008;Murad et al, 2009;Balistreri et al, 2010;Dossus et al, 2010;, including 14,282 cases and 16,277 controls. All 12 studies included were written in English.…”

“…Several studies were conducted to investigate the associations of PTGS2 rs20417 and rs689470 polymorphisms with PCa risk (Panguluri et al, 2004;Shahedi et al, 2006;Cheng et al, 2007;Danforth et al, 2008;Murad et al, 2009;Balistreri et al, 2010;Dossus et al, 2010;Wu et al, 2011). However, molecular epidemiological studies have yielded contradictory results concerning the potential roles of rs20417 and rs689470 polymorphisms in PCa.…”

Prostate cancer: genes, environment, immunity and the use of immunotherapy

“…Cyclooxygenase 2 is an enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. [34][35][36][37] Similarly, IkB kinase-a-activation reduces the infiltration of RANK ligand-expressing inflammatory cells and is associated with metastasis of prostate cancer in mice. 38 These observations suggest a combined role of gene, environment (macro and micro) and immunity in the development of prostate cancer.…”