Previous studies suggest that DNA-repair genetic polymorphisms may contribute to deficient DNA repair, elevated DNA damage, and prostate cancer (CaP) risk. In this study, we tested whether CaP risk and tumor aggressiveness are associated with 20 nsSNPs in three DNA-repair pathways: (1) Base Excision Repair (BER) - ADPRT, APE1, POLD1, and XRCC1; (2) Nucleotide Excision Repair (NER) - ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, hHR23B, and XPC; and (3) Mismatch Repair (MMR) - MLH1, MSH3, and MSH6. The gentomic DNA was extracted from whole blood collected in an ongoing, clinic-based, case-control study (623 cases and 646 controls). Genotyping was performed using the MassARRAY system (SEQUENOM Inc., San Diego, CA). In Caucasians, the CaP risk was significantly associated with ADPRT 762AA (OR=2.16, 95%CI=1.00-4.65), ERCC2 312NN (OR=0.66, 95%CI=0.44-0.99), and MSH3 940QQ (OR=3.51, 95%CI=1.27-9.74) genotypes after adjustment for age, family history (FH), smoking history, and benign prostatic hyperplasia (BPH). Although not significant, XRCC1 399QQ (OR=1.34, 95%CI=0.92-1.97) and ERCC4/XPF 415 QQ (OR=1.37, 95%CI=0.95-1.97) genotypes may also contribute to a slightly increased CaP risk. In Caucasian cases, ERCC2 312Nallele was associated with a more advanced tumor stage (OR=2.50, 95%CI=1.03-6.03) and a higher biopsy Gleason score (OR=2.08, 95%CI=1.03-4.20); XRCC1399QQ genotype was associated with a higher pre-treatment PSA (OR=3.09, 95%CI=1.16-8.21). In conclusion, this study provides evidence that nsSNPs in multiple repair pathways (BER, NER, and MMR) contribute to CaP susceptibility and tumor aggressiveness. Future studies are warranted to further evaluate to what extent genetic variants contribute to DNA-repair functional phenotype and CaP risk. (This study was supported by grants from the American Cancer Society, #CNE-101119 and the National Research Foundation, M01-RR07122)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]