ADP-ribosyltransferase (ADPRT) encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair (BER) pathway. Several single nucleotide polymorphisms (SNPs) in the ADPRT gene have been identified. This study tested whether prostate cancer risk is associated with an amino acid substitution variant, ADPRT V762A (T to C), using samples collected in an ongoing, clinic-based, case-control study (488 cases and 524 controls). In Caucasians, cancer cases (4%) had a slightly higher frequency of the AA-genotype compared to controls (2%). Prostate cancer risk is significantly associated with the AA-genotype compared to VV/VA as the referent group (odds ratio [OR]=2.54, 95% confidence interval [CI]=1.02-6.30, after adjustment for age, benign prostatic hyperplasia, smoking history, and family history). A higher percentage of younger cases (<65 years) carried the AA-genotype than older cases (>65) (6% vs. 3%, p=0.07), and a stronger association between the AA-genotype and prostate cancer risk was observed in younger subjects (OR=3.78; 95% CI=1.02-14.09) as compared to older cases (OR=1.78; 95% CI=0.48-6.54). Using peripheral lymphocytes from 331 cancer-free, healthy subjects, we also tested the functional significance of this variant. Intriguingly, AA-genotype carriers had a 37% decreased H2O2-induced ADPRT enzyme activity (mean+SD; 15229+7245 dpm/106 cells, n=13) compared to those with VV (22139+10662, n=289) and VA (17695.2+8236, n=94) genotypes (p=0.0001). This study is the first to demonstrate the role of the ADPRT V762A variant in its enzyme’s function and prostate cancer susceptibility.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]