Carcinogenesis Advance Access originally published online on March 28, 2006
Carcinogenesis 2006 27(9):1842-1848; doi:10.1093/carcin/bgl022
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Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk
1 Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, OH 44106, USA
2 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine Rochester, MN 55905, USA
3 Department of Family Medicine, Case Western Reserve University Cleveland, OH 44106, USA
4 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94143, USA
5 Department of Biostatistics and Research Epidemiology, Henry Ford Health System Detroit, MI 48202, USA
6 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation Cleveland, OH 44195, USA
*To whom correspondence should be addressed at: Department of Epidemiology and Biostatistics, University of California, San Francisco, 500 Parnassus Avenue, MU-420 West, San Francisco, CA 94143-0506, USA. Tel: +1 415 502 6882; Fax: +1 415 476 6014; Email: jwitte{at}itsa.ucsf.edu
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.
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