Prostate cancer risk and inflammation: Association with aspirin and other NSAID use & selected inflammation pathway-related gene polymorphisms.

摘要

Increasing evidence from epidemiologic and molecular studies suggests that chronic inflammation may be important in the development of prostate cancer (PCa). Several reports investigating the effects of NSAIDs have noted reduced relative risk of PCa among users of these anti-inflammatory medications, especially aspirin. We considered detailed measures of aspirin and other NSAID use in a population-based case-control study (Study I) conducted in King County, Washington with 1,001 incident cases diagnosed between January 1, 2002 and December 31, 2005 and 942 age-matched controls. Using unconditional logistic regression to estimate relative risk (OR) and 95% confidence intervals (95% CI), we found a significant 21% reduction in PCa risk among current users of aspirin compared to non-users (95% CI 0.65-0.96). Long-term aspirin use (>5 years) was also associated with decreased risk (OR=0.74, 95% CI 0.58-0.94), but this effect was limited to current users. More regular use was associated with the greatest reduction in relative risk, with an OR=0.70 (95% CI 0.55-0.90) for current users of daily low-dose aspirin. There was no evidence that the association between aspirin use and PCa risk varied by disease aggressiveness. Also, we found no relation with use of non-aspirin NSAIDs or acetaminophen.;In the second part of this dissertation, genotypes from 144 single nucleotide polymorphisms (SNPs) in selected inflammation pathway-related genes were evaluated for their relation with PCa risk. Incident cases from Study I and II (Caucasians n=1,308; African American n=149), aged 35-74, were compared with Study I and II controls (Caucasians n=1,266; African American n=85). Five SNPs in PTGS2, 2 in STAT3 and 1 each in CXCL12, IL4, IL6, IL6ST and TNF were significantly associated with PCa risk in Caucasian men. After correction for multiple testing, none remained significant. Four SNPs, IL4 rs2243228, IL6ST rs11574783, PTGS2 rs6685280 and STAT3 rs12949918, were independently associated with PCa, conferring a 3-fold elevation in relative risk in men carrying the maximum number of high-risk genotypes (OR=3.13, 95%Cl 1.50-6.54). SNPs in AKT1, PIK3R1 and STAT3 were independently associated with more aggressive PCa with a 5-fold (95% Cl 2.29-11.40) greater risk among carriers of all the high-risk genotypes.