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Prostate cancer (CaP) is the second leading cause of cancer death in American men. In addition to germline mutations, prostate tumor cells contain many somatic mutations, gene deletions and amplifications, chromosomal rearrangements, and changes in DNA methylation. We hypothesize that an accumulation of genetic abnormalities and a decline in DNA repair may lead to CaP development and progression. The objective of this study was to test whether germline nonsynonymous coding single nucleotide polymorphisms (nsSNP) of DNA-repair genes are associated with CaP recurrence. We tested 20 nsSNPs in 14 DNA-repair genes of 4 repair pathways, including: (i) Base Excision Repair: ADPRT V762A, APE1 D148E, POLD1 R19H/R119H, and XRCC1 R194W/R280H/R399Q; (ii) Nucleotide Excision Repair: ERCC2 D312N/ K751Q, ERCC4 R415Q, and ERCC5 D1104H; (iii) Mismatch Repair: MLH1 I219V, MSH3 R940Q/T1036A, and MSH6 G39E; and (iv) Double-Strand Break Repair: NBS1 Q185E and XRCC3 T241M. The genomic DNA was extracted from whole blood collected in an ongoing, clinic-based, case-control study. A total of 446 cases have confirmed 3.5-year follow-up data, and the CaP recurrence rate was 0.218. Approximately 90% of patients underwent treatment through either radiation therapy or radical prostatectomy. Genotyping was performed using the MassARRAY system (SEQUENOM Inc., San Diego, CA). For exploring potential gene-gene interaction, Multivariate Adaptive Regression Splines (MARS)-logit method with a hybrid data-mining approach was applied. The CaP recurrence was significantly associated with MSH3 1036TA/AA (OR=4.13, 95%CI=1.76-9.68), the genotype combination of ERCC5 1103DD and XRCC1 280RH/HH (OR=4.57, 95%CI=1.42-14.73), or the combination of MSH3 1036TT, XRCC3 241 TM/MM and ERCC2 312 DN/NN (OR=3.22, 95%CI=1.66-6.26), after adjusting for family history, smoking history, diagnosis age, and follow-up time. In conclusion, gene-gene interactions of DNA-repair nsSNPs in multiple repair pathways contributed to CaP recurrence. However, we must note that sample size and short follow-up duration may have limited our study’s power for assessing gene-gene interactions in CaP recurrence. Larger studies and longer follow-up are clearly warranted to further test DNA-repair nsSNPs in CaP recurrence. (Supported by American Cancer Society, CNE-101119)

[Proc Amer Assoc Cancer Res, Volume 47, 2006]