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XRCC1 Polymorphisms: Effects on Aflatoxin B₁-DNA Adducts and Glycophorin A Variant Frequency

Laboratory of Computational Biology and Risk Assessment [R. M. L., D. A. B.] and Division of Extramural Research and Training [C. L. T.], National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Lawrence Livermore National Laboratory, Livermore, California 94550 [R. G. L.]; and Department of Public Health, Chang Gung College, Kwei-San, Tao-Yuan, Taiwan, Republic of China 10018 [L. L. H.]

Hereditary genetic defects in DNA repair lead to increased risk of cancer. Polymorphisms in several DNA repair genes have been identified; however, the impact on repair phenotype has not been elucidated. We explored the relationship between polymorphisms in the DNA repair enzyme, XRCC1 (codons 194, 280, and 399), and genotoxic end points measured in two populations: (a) placental aflatoxin B₁ DNA (AFB₁-DNA) adducts in a group of Taiwanese maternity subjects (n = 120); and (b) somatic glycophorin A (GPA) variants in erythrocytes from a group of North Carolina smokers and nonsmokers (n = 59). AFB₁-DNA adducts were measured by ELISA, and erythrocyte GPA variant frequency (NN and NØ) was assessed in MN heterozygotes with a flow cytometric assay. XRCC1 genotypes were identified by PCR-RFLPs. The XRCC1 399Gln allele was significantly associated with higher levels of both AFB₁-DNA adducts and GPA NN mutations. Individuals with the 399Gln allele were at risk for detectable adducts (odds ratio, 2.4; 95% confidence interval, 1.1–5.4; P = 0.03). GPA NN variant frequency was significantly higher in 399Gln homozygotes (19.6 x 10^-6) than in Gln/Arg heterozygotes (11.4 x 10^-6; P < 0.05) or Arg/Arg homozygotes (10.1 x 10^-6; P = 0.01). No significant effects were observed for other XRCC1 polymorphisms. These results suggest that the Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in deficient DNA repair.

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				R. M. Taylor, A. Thistlethwaite, and K. W. Caldecott Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair Mol. Cell. Biol., April 15, 2002; 22(8): 2556 - 2563. [Abstract] [Full Text] [PDF]

				J. Y. Park, S. Y. Lee, H.-S. Jeon, N. C. Bae, S. C. Chae, S. Joo, C. H. Kim, J.-H. Park, S. Kam, I. S. Kim, et al. Polymorphism of the DNA Repair Gene XRCC1 and Risk of Primary Lung Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 23 - 27. [Abstract] [Full Text]

				H. H. Nelson, K. T. Kelsey, L. A. Mott, and M. R. Karagas The XRCC1 Arg399Gln Polymorphism, Sunburn, and Non-melanoma Skin Cancer: Evidence of Gene-Environment Interaction Cancer Res., January 1, 2002; 62(1): 152 - 155. [Abstract] [Full Text] [PDF]

				G. Matullo, D. Palli, M. Peluso, S. Guarrera, S. Carturan, E. Celentano, V. Krogh, A. Munnia, R. Tumino, S. Polidoro, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects Carcinogenesis, September 1, 2001; 22(9): 1437 - 1445. [Abstract] [Full Text] [PDF]

				J. J. Hu, T. R. Smith, M. S. Miller, H. W. Mohrenweiser, A. Golden, and L.D. Case Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity Carcinogenesis, June 1, 2001; 22(6): 917 - 922. [Abstract] [Full Text] [PDF]

				M. E. Smela, S. S. Currier, E. A. Bailey, and J. M. Essigmann The chemistry and biology of aflatoxin B1: from mutational spectrometry to carcinogenesis Carcinogenesis, April 1, 2001; 22(4): 535 - 545. [Abstract] [Full Text] [PDF]

				D. Butkiewicz, M. Rusin, L. Enewold, P. G. Shields, M. Chorazy, and C. C. Harris Genetic polymorphisms in DNA repair genes and risk of lung cancer Carcinogenesis, April 1, 2001; 22(4): 593 - 597. [Abstract] [Full Text] [PDF]

				H. Shen, E. M. Sturgis, S. G. Khan, Y. Qiao, T. Shahlavi, S. A. Eicher, Y. Xu, X. Wang, S. S. Strom, M. R. Spitz, et al. An Intronic Poly (AT) Polymorphism of the DNA Repair Gene XPC and Risk of Squamous Cell Carcinoma of the Head and Neck: A Case-Control Study Cancer Res., April 1, 2001; 61(8): 3321 - 3325. [Abstract] [Full Text]

				E. J. Duell, R. C. Millikan, G. S. Pittman, S. Winkel, R. M. Lunn, C.-K. J. Tse, A. Eaton, H. W. Mohrenweiser, B. Newman, and D. A. Bell Polymorphisms in the DNA Repair Gene XRCC1 and Breast Cancer Cancer Epidemiol. Biomarkers Prev., March 1, 2001; 10(3): 217 - 222. [Abstract] [Full Text]

				D. Ratnasinghe, S.-X. Yao, J. A. Tangrea, Y.-L. Qiao, M. R. Andersen, M. J. Barrett, C. A. Giffen, Y. Erozan, M. S. Tockman, and P. R. Taylor Polymorphisms of the DNA Repair Gene XRCC1 and Lung Cancer Risk Cancer Epidemiol. Biomarkers Prev., February 1, 2001; 10(2): 119 - 123. [Abstract] [Full Text]

				M. C. Stern, D. M. Umbach, C. H. van Gils, R. M. Lunn, and J. A. Taylor DNA Repair Gene XRCC1 Polymorphisms, Smoking, and Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., February 1, 2001; 10(2): 125 - 131. [Abstract] [Full Text]

				M. Z. Hadi, M. A. Coleman, K. Fidelis, H. W. Mohrenweiser, and D. M. Wilson III Functional characterization of Ape1 variants identified in the human population Nucleic Acids Res., October 15, 2000; 28(20): 3871 - 3879. [Abstract] [Full Text] [PDF]

				E. J. Duell, J. K. Wiencke, T.-J. Cheng, A. Varkonyi, Z. F. Zuo, T. D. S. Ashok, E. J. Mark, J. C. Wain, D. C. Christiani, and K. T. Kelsey Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells Carcinogenesis, May 1, 2000; 21(5): 965 - 971. [Abstract] [Full Text] [PDF]

				F. P. Perera Molecular Epidemiology: On the Path to Prevention? J Natl Cancer Inst, April 19, 2000; 92(8): 602 - 612. [Abstract] [Full Text] [PDF]

				F. P. Perera and I.B. Weinstein Molecular epidemiology: recent advances and future directions Carcinogenesis, March 1, 2000; 21(3): 517 - 524. [Abstract] [Full Text] [PDF]

				E. M. Sturgis, E. J. Castillo, L. Li, R. Zheng, S. A. Eicher, G. L. Clayman, S. S. Strom, M. R. Spitz, and Q. Wei Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck Carcinogenesis, November 1, 1999; 20(11): 2125 - 2129. [Abstract] [Full Text] [PDF]

				R. M. Santella Immunological Methods for Detection of Carcinogen-DNA Damage in Humans Cancer Epidemiol. Biomarkers Prev., September 1, 1999; 8(9): 733 - 739. [Full Text]