To date, the potential impact of
hormones on
prostate cancer has predominantly focused on receptor-mediated events. However,
catechol estrogens, if not inactivated by
catechol-O-methyltransferase (COMT), can generate large quantities of
reactive oxygen species (ROS). ROS may cause a spectrum of damage including oxidative
DNA base lesions, which can lead to irreversible mutation(s) if they are not repaired by base excision repair (BER) systems. hOGG1 is a key
enzyme in short patch BER because it recognizes and performs initial excision of the most common form of oxidative
DNA base damage,
8-hydroxyguanine (8-oxo-dG). To investigate potential non-receptor-mediated
estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and
prostate cancer in a family-based case-control study (439
prostate cancer cases, 479 brother controls). We observed no noteworthy associations between these polymorphisms and
prostate cancer risk in the total study population. However, among men with more aggressive
prostate cancer, the hOGG1 326
Cys/Cys genotype was inversely associated with disease (OR=0.30; 95% CI=0.09-0.98). Combining the lower activity CYP1B1 432
Leu/Leu or Leu/Val genotypes (which may decrease the level of
catechol estrogens and ROS generated) with the hOGG1 326
Cys/Cys genotype and the XRCC1 399
Arg/Arg or
Arg/Gln genotypes (which may enhance BER) resulted in an even further reduced risk in Caucasians with more aggressive disease (OR=0.09; 95% CI=0.01-0.56). Including the high-activity COMT 158Val allele to this combination also lowered aggressive
prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88). The decreased risk we observed with the hOGG1 326
Cys/Cys genotype confirms an earlier report and the further reduced risk found with the CYP1B1 (432
Leu/Leu or Leu/Val)-hOGG1 (326
Cys/Cys)-XRCC1 (
Arg/Arg or
Arg/Gln) genotype combination may lend new insights to the importance of ROS generated from non-receptor-mediated estrogenic mechanisms in more aggressive
prostate cancer.