The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNAbinding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08 -6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (>65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H 2 O 2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean ؎ SD dpm/10 6 cells) were 18,554 ؎ 9,070 (n ‫؍‬ 257), 14,847 ؎ 7,082 (n ‫؍‬ 86), and 12,155 ؎ 6,334 (n ‫؍‬ 11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.

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This study used the alkaline Comet assay to evaluate whether basal or H2O2-induced DNA damage is associated with prostate cancer (CaP) risk. Using lymphocyte samples from 158 CaP cases and 128 controls, collected in an ongoing case-control study, our results showed that basal DNA damage did not differ between cases and controls. However, the H2O2-induced DNA damage level was significantly higher in incident cases (mean +/- SD; 6.61 +/- 4.43, n = 102) than controls (5.30 +/- 3.60, n = 128) or prevalent cases (4.47 +/- 3.19; n = 56). Incident cases with a positive smoking history had significantly higher H2O2-induced DNA damage than never-smokers (7.57 +/- 4.82 versus 4.52 +/- 2.40; P < 0.001). Above-median H2O2-induced DNA damage was associated with a 1.61-fold increase in CaP risk [95% confidence interval (CI) = 0.92-2.81], after adjustment for age, race, benign prostatic hyperplasia (BPH), smoking history and family history (FH). Using the lowest quartile of H2O2-induced DNA damage as the referent group, the adjusted ORs for the 25th, 50th and 75th quartiles were 0.90 (95% CI = 0.39-2.05), 1.06 (95% CI = 0.48-2.35) and 2.05 (95% CI = 0.96-4.37), respectively (P = 0.046, test for linear trend). The association between CaP and DNA damage was modified by age, smoking history, family history and body mass index. Our results suggest that DNA damage may be associated with CaP risk. However, larger case-control and follow-up studies are warranted to further evaluate the potential application of the alkaline Comet assay in CaP risk assessment and prevention.

The ADP-ribosyltransferase (ADPRT) gene encodes the poly(ADP-ribose)polymerase-1 (PARP-1) enzyme, which plays critical roles in DNA-damage signaling and repair, cell death, maintenance of genomic stability, and carcinogenesis. It may also serve as a potential target for cancer therapy. In this review, we evaluate findings from animal model systems and molecular epidemiological studies to demonstrate the potential role of ADPRT/PARP-1 in aging and carcinogenesis. With increasing interest in associating human cancer risk with single nucleotide polymorphisms (SNPs) and/or dysfunction of ADPRT/PARP-1, several important technical challenges will need to be overcome. These challenges include developing specific functional assays, selecting SNPs with potential functional impact, and exploring statistical methods for gene-gene and gene-environmental interactions. Therefore, this review also highlights strategies to evaluate the functional significance of ADPRT/PARP-1 SNPs in human cancer risk assessment. In summary, dysfunction of PARP-1 may play a critical role in abnormal cellular functions; its molecular mechanism in aging and cancer susceptibility is an issue which needs urgently to be elucidated.

Genetic variations in cell cycle checkpoints and DNA repair genes are associated with prolonged cell cycle G 2 delay following ionizing radiation (IR) treatment and breast cancer risk. However, different studies reported conflicting results examining the association between post-IR cell cycle delay and breast cancer risk utilizing four different parameters: cell cycle G 2 delay index, %G 2-M, G 2 /G 0-G 1 , and (G 2 /G 0-G 1)/S. Therefore, we evaluated whether different parameters may influence study results using a data set from 118 breast cancer cases and 225 controls as well as lymphoblastoid and breast cancer cell lines with different genetic defects. Our results suggest that cell cycle G 2 delay index may serve as the best parameter in assessing breast cancer risk, genetic regulation of IR-sensitivity, and mutations of ataxia telangiectasia mutated (ATM) and TP53. Cell cycle delay in 21 lymphoblastoid cell lines derived from BRCA1 mutation carriers was not different from that in controls. We also showed that IR-induced DNA-damage signaling, as measured by phosphorylation of H2AX on serine 139 (γ-H2AX) was inversely associated with cell cycle G 2 delay index. In summary, the cellular responses to IR are extremely complex; mutations or genetic variations in DNA damage signaling, cell cycle checkpoints, and DNA repair contribute to cell cycle G 2 delay and breast cancer risk. The cell cycle G 2 delay assay characterized in this study may help identify subpopulations with elevated risk of breast cancer or susceptibility to adverse effects in normal tissue following radiotherapy.

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