This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lockett, K. L. Articles by Hu, J. J. Search for Related Content PubMed PubMed Citation Articles by Lockett, K. L. Articles by Hu, J. J.

The ADPRT V762A Genetic Variant Contributes to Prostate Cancer Susceptibility and Deficient Enzyme Function

¹ Departments of Cancer Biology, ² Public Health Sciences, and ³ Urology and ⁴ Center for Human Genomics, and ⁵ Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and ⁶ Division of Epidemiology, University of New Mexico, Albuquerque, New Mexico

The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding 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 H₂O₂ in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean ± SD dpm/10⁶ 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.

This article has been cited by other articles:

				T. R. Smith, E. A. Levine, R. I. Freimanis, S. A. Akman, G. O. Allen, K. N. Hoang, W. Liu-Mares, and J. J. Hu Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk Carcinogenesis, November 1, 2008; 29(11): 2132 - 2138. [Abstract] [Full Text] [PDF]

				F.-Y. Chiang, C.-W. Wu, P.-J. Hsiao, W.-R. Kuo, K.-W. Lee, J.-C. Lin, Y.-C. Liao, and S.-H. H. Juo Association between Polymorphisms in DNA Base Excision Repair Genes XRCC1, APE1, and ADPRT and Differentiated Thyroid Carcinoma Clin. Cancer Res., September 15, 2008; 14(18): 5919 - 5924. [Abstract] [Full Text] [PDF]

				R. Gao, D. K. Price, T. Sissung, E. Reed, and W. D. Figg Ethnic disparities in Americans of European descent versus Americans of African descent related to polymorphic ERCC1, ERCC2, XRCC1, and PARP1 Mol. Cancer Ther., May 1, 2008; 7(5): 1246 - 1250. [Abstract] [Full Text] [PDF]

				J. M. Hoskins, E. Marcuello, A. Altes, S. Marsh, T. Maxwell, D. J. Van Booven, L. Pare, R. Culverhouse, H. L. McLeod, and M. Baiget Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes Clin. Cancer Res., March 15, 2008; 14(6): 1788 - 1796. [Abstract] [Full Text] [PDF]

				M. C. Stern, D. V. Conti, K. D. Siegmund, R. Corral, J.-M. Yuan, W.-P. Koh, and M. C. Yu DNA Repair Single-Nucleotide Polymorphisms in Colorectal Cancer and their Role as Modifiers of the Effect of Cigarette Smoking and Alcohol in the Singapore Chinese Health Study Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2363 - 2372. [Abstract] [Full Text] [PDF]

				M. Emonts, R. H. Veenhoven, S. P. Wiertsema, J. J. Houwing-Duistermaat, V. Walraven, R. d. Groot, P. W.M. Hermans, and E. A.M. Sanders Genetic Polymorphisms in Immunoresponse Genes TNFA, IL6, IL10, and TLR4 Are Associated With Recurrent Acute Otitis Media Pediatrics, October 1, 2007; 120(4): 814 - 823. [Abstract] [Full Text] [PDF]

				S. I. Berndt, W.-Y. Huang, M. D. Fallin, K. J. Helzlsouer, E. A. Platz, J. L. Weissfeld, T. R. Church, R. Welch, S. J. Chanock, and R. B. Hayes Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma Cancer Res., February 1, 2007; 67(3): 1395 - 1404. [Abstract] [Full Text] [PDF]

				C. Li, Z. Liu, L.-E Wang, S. S. Strom, J. E. Lee, J. E. Gershenwald, M. I. Ross, P. F. Mansfield, J. N. Cormier, V. G. Prieto, et al. Genetic variants of the ADPRT, XRCC1 and APE1 genes and risk of cutaneous melanoma Carcinogenesis, September 1, 2006; 27(9): 1894 - 1901. [Abstract] [Full Text] [PDF]

				K. L. Lockett, M.C. Hall, P. E. Clark, S.-C. Chuang, B. Robinson, H.-Y. Lin, L.J. Su, and J. J. Hu DNA damage levels in prostate cancer cases and controls Carcinogenesis, June 1, 2006; 27(6): 1187 - 1193. [Abstract] [Full Text] [PDF]

				Z. Zhang, J. Wan, X. Jin, T. Jin, H. Shen, D. Lu, and Z. Xia Genetic Polymorphisms in XRCC1, APE1, ADPRT, XRCC2, and XRCC3 and Risk of Chronic Benzene Poisoning in a Chinese Occupational Population Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2614 - 2619. [Abstract] [Full Text] [PDF]

				M. Shiokawa, M. Masutani, H. Fujihara, K. Ueki, R. Nishikawa, T. Sugimura, H. Kubo, and H. Nakagama Genetic Alteration of Poly(ADP-ribose) Polymerase-1 in Human Germ Cell Tumors Jpn. J. Clin. Oncol., February 1, 2005; 35(2): 97 - 102. [Abstract] [Full Text] [PDF]

				X. Zhang, X. Miao, G. Liang, B. Hao, Y. Wang, W. Tan, Y. Li, Y. Guo, F. He, Q. Wei, et al. Polymorphisms in DNA Base Excision Repair Genes ADPRT and XRCC1 and Risk of Lung Cancer Cancer Res., February 1, 2005; 65(3): 722 - 726. [Abstract] [Full Text] [PDF]