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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.]

	ABSTRACT

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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.

	Introduction

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Hereditary genetic defects in DNA repair lead to a marked increased risk of developing cancer. Although DNA repair deficiency often arises from mutations in genes that result in a loss of the DNA repair protein, DNA polymorphisms may alter the structure of the DNA repair enzyme and modulate cancer susceptibility. Mutations and polymorphisms have been identified in many of the genes coding for DNA repair enzymes such as XRCC1² (1, 2, 3) . XRCC1 was identified by its ability to restore DNA repair activity in the Chinese hamster ovary cell lines, EM-9 and EM-11, which are hypersensitive to ionizing radiation and alkylating agents (4, 5, 6) . These cells have increased spontaneous and mutagen-induced sister chromatid exchange and have defects in rejoining single-strand breaks after exposure to X-ray (6 , 7) . Both EM-9 and EM-11 cells contain a mutated XRCC1 gene and lack XRCC1 protein (8) .

Ionizing radiation and alkylating agents cause DNA base damage and strand breaks that elicit BER. The XRCC1 protein complexes with DNA ligase III via a BRCT domain in its COOH terminus and with DNA polymerase ß via the XRCC1 NH₂ terminus domain to repair gaps left during BER (9) . PARP detects DNA strand breaks induced by ionizing radiation and is believed to participate in BER (10) . XRCC1 negatively regulates PARP by binding to it via the XRCC1 central domain (amino acids 301–402; Ref. 11 ). This central region also includes a BRCT domain and shares homology to the yeast rad4/cut5 DNA repair gene (11 , 12) . Functional importance of this region is also suggested by the determination that the DNA repair-deficient EM-11 cell line contains a cysteine-to-tyrosine mutation at codon 390 (8) .

Shen et al. (1) identified three coding polymorphisms in the XRCC1 gene at codons 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln). These polymorphisms code for nonconservative amino acid changes (including the Arg399Gln change in the PARP binding domain), which suggests potential functional relevance, but their impact on phenotype is unknown. We tested whether XRCC1 polymorphisms were associated with higher levels of genotoxic damage and found that the 399 Gln allele was significantly associated with higher levels of AFB₁-DNA adducts and GPA somatic mutations.

	Materials and Methods

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Subjects.
AFB₁-DNA adducts and XRCC1 genotypes were assessed in 120 placental DNA samples obtained from uncomplicated pregnancies at Taipei Chang Gung Memorial Hospital as described by Hsieh and Hsieh (13) . Sixty placentas were collected during high (summer) and low (winter) exposure season. GPA VF was measured in erythrocyte samples obtained from 49 smokers and 10 nonsmokers (17 blacks and 42 whites) heterozygous for the GPA antigen. The subjects were part of a community-based sample comprised of 294 healthy unrelated blacks and whites from Durham and Chapel Hill, North Carolina. This sample population has been used in other genotyping and exposure studies (14 , 15) . XRCC1 genotypes were determined using genomic DNA isolated from lymphocytes. One hundred and ten additional whites and 81 additional blacks from the same community sample were included in the genotyping studies to compare XRCC1 allele frequency in different ethnic groups.

Detection of AFB₁-DNA Adducts.
AFB₁-DNA adduct levels were measured by competitive ELISA using monoclonal antibody 6A10 and 50 µg of DNA as described previously (16) . The percent of inhibition was calculated by comparison with the nonmodified heat-denatured calf thymus DNA control. DNA samples were quantified relative to an imidazole ring-opened AFB₁-DNA standard, which has a modification level of 4 adducts/10⁵ nucleotide. Values below 20% inhibition, corresponding to 0.5 µmol/mol DNA, were considered not detectable. Each sample was measured in triplicate on three different assay dates and had a variability of less than 10%.

Measurement of GPA Variants in Erythrocytes.
Blood samples were typed for the M and N antigens using commercial sera (Ortho Diagnostics, Raritan, NJ) to determine MN heterozygous individuals. Fifty-nine individuals were identified and assessed for variants (NØ and NN) using the BR6 version of the GPA assay as described previously (17 , 18) . A total of 5 x 10⁶ erythrocytes were analyzed for each sample.

XRCC1 Genotyping.
XRCC1 genotypes were detected using a PCR-RFLP technique. A multiplex PCR was used to amplify 491 bp and 615 bp of DNA fragments containing the codon 194 and 399 polymorphisms, respectively. Primers were: (a) 26106F gcc ccg tcc cag gta and 26577R agc ccc aag acc ctt tca ct for codon 194; and (b) 27776F ttg tgc ttt ctc tgt gtc ca and 28371R tcc tcc agc ctt ttc tga ta for codon 399. A separate PCR using primers 27405F ttg acc ccc agt ggt gct aa and 28247R cgc tgg gac cac ctg tgt t were used to amplify the 861-bp DNA fragment containing the codon 280 polymorphism. PCR conditions for both methods consisted of 50 ng of genomic DNA, 3 mM MgCl₂, 200 µM each dNTPS, 0.5 units Taq (Promega, Madison, WI) + TaqStart Antibody (Sigma, St. Louis, MO), and either 0.6 µM (codon 194) or 0.8 µM (codon 280 and 399) each primer in 1x PCR buffer (Promega). PCR program was a 4-min denaturation step at 94°C followed by 30 cycles of 30 s at 94°C and 90 s at 68°C. The Arg allele at codon 194 and the Arg allele at codon 399 both create MspI sites. The multiplex 491-bp and 615-bp PCR products (codons 194 and 399, respectively) were digested at 37°C for 2 h and resolved on 3% Metaphor agarose gels (FMC Bioproducts, Rockland, ME; see Fig. 1A ). A 174-bp fragment was present in all of the samples because of an invariant MspI site (in the 491-bp fragment) that served as an internal control for complete digestion. The Arg/Arg, Arg/Trp, and Trp/Trp genotypes for codon 194 resulted in 21-bp and 292-bp; 21-bp, 292-bp, and 313-bp; and 313-bp digestion products, respectively. The Gln allele (codon 399) was distinguished from the Arg allele as an undigested fragment (615-bp) compared with the 221- and 374-bp digested fragments of the Arg allele. RspI digestion of the 861-bp PCR containing codon 280 was incubated separately at 37°C for 2 h. The digestion fragments—60-bp, 221-bp, 580-bp, and 640-bp—were separated on 2% 3:1 NuSieve agarose gels (FMC Bioproducts; see Fig. 1B ). The Arg allele creates a RspI site at nucleotide 27466 and results in the 580-bp and 60-bp products that are not recognized by the allele but is contained in the 640-bp fragment. The 221-bp fragment is a result of an invariant RspI site present in all of the samples.

View larger version (44K): [in this window] [in a new window]   Fig. 1. A, 3% Metaphor gel on MspI digestion of the multiplex XRCC1 PCR products containing codons 194 and 399. Codon 194 and 399 genotypes are indicated above and below the Lanes, respectively. Uncut, the two undigested products (491-bp and 615-bp, codons 194 and 399, respectively). Representative wild-type homozygotes (Arg/Arg and Arg/Arg, 194 and 399, respectively), heterozygotes (Arg/Trp and Arg/Gln, 194 and 399 respectively), and variant homozygotes (Trp/Trp and Gln/Gln, 194 and 399, respectively) are shown for each polymorphism. M, 100-bp molecular weight standard (Promega). B, 2% NuSieve gel on RspI digestion of XRCC1 PCR product containing codon 280. Uncut, depicts the 861-bp PCR product. Wild-type homozygotes (Arg/Arg) and heterozygotes (Arg/His) are shown.

	Results and Discussion

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Estimated genotype and allele frequencies for XRCC1 polymorphisms in black, white, and Taiwanese population samples are given in Table 1 . All of the distributions were in Hardy-Weinberg equilibrium. The 194Trp and 280His alleles were at a low frequency in blacks [0.05 (194Trp) and 0.02 (280His)] and whites [0.06 (194Trp) and 0.03 (280His)] but were significantly more prevalent in Taiwanese [0.27 (194Trp) and 0.11 (280His) P < 0.001]. The 399Gln-allele frequency was significantly different among all of the three populations with the Gln allele occurring the highest in whites (0.37), intermediate in Taiwanese (0.26) and lowest in blacks (0.17; Table 1 ). Shen et al. (1) estimated variant allele frequency of 0.25 (194Trp), 0.08 (280His) and 0.25 (399Gln) by sequencing the XRCC1 gene from 12 unidentified individuals. These frequencies are most similar to that observed in the Taiwanese population (Table 1) .

AFB₁ mediates its carcinogenicity mainly through the formation of AFB₁-guanine adducts. These highly unstable adducts can either form more stable ring-opened structures or undergo spontaneous depurination, resulting in apurinic sites and eliciting BER (19, 20, 21) . Administration of AFB₁ in rats causes single-strand breaks and increases PARP, DNA ligase, and DNA polymerase ß enzyme activity (20) . These enzymes interact with XRCC1 during BER, suggesting that XRCC1 may be important in the repair of AFB₁-DNA adducts. Thus, the association of AFB₁-DNA adducts and the 399Gln allele is biologically plausible. Moreover, codon 399 is located in the PARP-binding region of the XRCC1 gene. The specific functional effect of the Arg399Gln change on XRCC1 binding with PARP remains to be explored.

Although the 399Gln allele of XRCC1 was related to the detection of AFB₁-DNA adducts, the effect seems to be greatest at lower adduct levels (Table 3) . Possibly, in tissues with higher levels of AFB₁-DNA adducts, the BER pathway may become saturated, which would tend to reduce differences between functional and less functional alleles. A similar phenomena has been observed in rodent exposure studies in which very high levels of AFB₁-induced DNA damage resulted in a decline of PARP activity. (20) .

Differences in AFB₁-DNA adducts also reflect differences in exposure. External exposure information was not available for the subjects so that the direct effects of adduct repair cannot be assessed. In vitro or in vivo studies using a fixed AFB₁ exposure should provide insight into the effect of genotype on the repair of AFB₁-DNA adducts.

We also examined the relationship of XRCC1 genotypes and somatic mutations characterized by the GPA assay (Table 4) . The GPA assay detects two types of allele loss variants NØ (allele loss) and NN (allele loss and duplication) present in erythrocytes. We measured the VF of both NØ and NN mutations in smokers and nonsmokers who were heterozygous for GPA. The mean VF (NØ and NN) was estimated for individuals with the different XRCC1 genotypes (codons 194, 280, and 399) using a LS regression model adjusting for smoking and age (Table 4) . Smoking did not affect VF for either NØ (P = 0.13) or NN (P = 0.31). Age was associated with increased NN VF (P = 0.005) but not NØ VF (P = 0.26). The LS mean NN VF was highest in individuals with two Gln alleles (Gln/Gln, 19.6 x 10^-6), intermediate with one Gln allele (Arg/Gln, 11.4 x 10^-6), and lowest with no Gln alleles (Arg/Arg, 10.1 x 10^-6). Differences in LS mean VF were significant (P < 0.05) when compared with the Gln/Gln genotype. The association between the 399 genotypes and mean GPA VF was greater in smokers than in nonsmokers. NØ VF was similar in all of the 399 genotypes. The 194Trp allele and 280His allele did not significantly affect either NØ or NN VF; however, these alleles are rare in the GPA study population (whites and blacks), which limits the interpretation of this negative finding.

GPA VF is a marker of DNA damage and increases after exposure to ionizing radiation, benzene, chemotherapy, and other mutagens (22 , 23) . Individuals with diseases of DNA repair and metabolisms, such as ataxia telangiectasia and Bloom Syndrome, have significant elevations in GPA VF, thus implicating it as a marker of exposure, damage, and cancer risk (22) . NØ and NN variants arise from independent molecular mechanisms (22) . Gene inactivation mechanisms such as point mutations, deletions, and chromosome loss are likely to result in NØ variants, whereas mitotic recombination, gene conversion, and chromosome missegregation are more important in generating NN variants (23) . The relationship of 399Gln allele to NN but not NØ variants may result from a greater role of the central domain of XRCC1 in recombination repair than repair of lesions that cause gene inactivation. Both PARP and XRCC1 participate in DNA strand-break rejoining and homologous recombination (7 , 24, 25, 26) . Cells without the XRCC1 gene and mice lacking the PARP gene exhibit high levels of sister chromatid exchange, which suggests increased recombination activity (7 , 26) . PARP inhibitors cause an increase in recombination frequency and genomic instability (27) , and XRCC1 expression is elevated during male meiosis in the mouse, which implies a role in meiotic recombination (28) .

This is the first report to investigate associations between phenotype (measures of genotoxic damage) and three missense polymorphisms—194(Arg to Trp), 280 (Arg to His), and 399 (Arg to Gln)—in the XRCC1 gene. We find evidence to suggest that the XRCC1 399Gln allele is associated with increased levels of DNA damage that may be due to reduced DNA repair function. Individuals with the Gln allele were more likely to have higher levels of AFB₁-DNA adducts and GPA NN somatic variants. BER is important in the repair of AFB₁-DNA adducts, whereas errors in recombination may generate GPA NN variants. XRCC1 is implicated in both of the repair processes. Moreover, the Arg399Gln polymorphism occurs in a region of the XRCC1 gene that contains biologically important domains (PARP binding and BRCT) and has homology with another DNA repair-related gene (yeast rad4/cut5 gene). Future studies need to characterize the role of the XRCC1 399Gln allele in functional DNA repair assays and to test to see whether it affects the levels of other biomarkers of DNA damage.

	ACKNOWLEDGMENTS

 
We thank Drs. Harvey Mohrenweiser and Richard Shen for sharing information about XRCC1 polymorphisms. We also thank the following: Richard Morris and Dr. Xugang Guo for assistance with statistical analysis; Kathleen Bones for technical support; and Gary Pittman and Dr. William Kaufmann for critical review of the manuscript.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at LCBRA, National Institute of Environmental Health Sciences, MD C3-03, P. O. Box 12233, Research Triangle Park, NC 27709. E-mail: BELL1{at}niehs.nih.gov

² The abbreviations used are: XRCC1, X-ray repair cross-complementing 1; BER, base excision repair; BRCT, BRCA1 COOH terminus; PARP, poly (ADP-ribose) polymerase; AFB₁, aflatoxin B₁; GPA, glycophorin A; OR, odds ratio; CI, confidence interval; VF, variant frequency; LS, least square(s).

Received 2/ 4/99. Accepted 4/16/99.

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				T. van der Straaten, D. Kweekel, M. Tiller, J. Bogaartz, and H.-J. Guchelaar Multiplex Pyrosequencing of Two Polymorphisms in DNA Repair Gene XRCC1 J. Mol. Diagn., September 1, 2006; 8(4): 444 - 448. [Abstract] [Full Text] [PDF]

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				X. Wu, J. Gu, T.-T. Wu, S. G. Swisher, Z. Liao, A. M. Correa, J. Liu, C. J. Etzel, C. I. Amos, M. Huang, et al. Genetic Variations in Radiation and Chemotherapy Drug Action Pathways Predict Clinical Outcomes in Esophageal Cancer J. Clin. Oncol., August 10, 2006; 24(23): 3789 - 3798. [Abstract] [Full Text] [PDF]

				G. Matullo, A.M. Dunning, S. Guarrera, C. Baynes, S. Polidoro, S. Garte, H. Autrup, C. Malaveille, M. Peluso, L. Airoldi, et al. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study Carcinogenesis, May 1, 2006; 27(5): 997 - 1007. [Abstract] [Full Text] [PDF]

				A. Ruzzo, F. Graziano, K. Kawakami, G. Watanabe, D. Santini, V. Catalano, R. Bisonni, E. Canestrari, R. Ficarelli, E. T. Menichetti, et al. Pharmacogenetic Profiling and Clinical Outcome of Patients With Advanced Gastric Cancer Treated With Palliative Chemotherapy J. Clin. Oncol., April 20, 2006; 24(12): 1883 - 1891. [Abstract] [Full Text] [PDF]

				B. F. Pachkowski, S. Winkel, Y. Kubota, J. A. Swenberg, R. C. Millikan, and J. Nakamura XRCC1 Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between XRCC1 Codon 280 His and Smoking. Cancer Res., March 1, 2006; 66(5): 2860 - 2868. [Abstract] [Full Text] [PDF]

				K. Ekstrom Smedby, C. M. Lindgren, H. Hjalgrim, K. Humphreys, C. Schollkopf, E. T. Chang, G. Roos, L. P. Ryder, K. I. Falk, J. Palmgren, et al. Variation in DNA Repair Genes ERCC2, XRCC1, and XRCC3 and Risk of Follicular Lymphoma. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 258 - 265. [Abstract] [Full Text] [PDF]

				C.-C. Chen, S.-Y. Yang, C.-J. Liu, C.-L. Lin, Y.-F. Liaw, S.-M. Lin, S.-D. Lee, P.-J. Chen, C.-J. Chen, and M.-W. Yu Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma Int. J. Epidemiol., December 1, 2005; 34(6): 1310 - 1318. [Abstract] [Full Text] [PDF]

				R. J. Hung, J. Hall, P. Brennan, and P. Boffetta Genetic Polymorphisms in the Base Excision Repair Pathway and Cancer Risk: A HuGE Review Am. J. Epidemiol., November 15, 2005; 162(10): 925 - 942. [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. Majumder, N. Sikdar, R. R. Paul, and B. Roy Increased Risk of Oral Leukoplakia and Cancer Among Mixed Tobacco Users Carrying XRCC1 Variant Haplotypes and Cancer Among Smokers Carrying Two Risk Genotypes: One on Each of Two Loci, GSTM3 and XRCC1 (Codon 280) Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2106 - 2112. [Abstract] [Full Text] [PDF]

				A. G. Casson, Z. Zheng, S. C. Evans, P. J. Veugelers, G. A. Porter, and D. L. Guernsey Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma Carcinogenesis, September 1, 2005; 26(9): 1536 - 1541. [Abstract] [Full Text] [PDF]

				Y. Guo, L. L. Breeden, H. Zarbl, B. D. Preston, and D. L. Eaton Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage Mol. Cell. Biol., July 15, 2005; 25(14): 5823 - 5833. [Abstract] [Full Text] [PDF]

				Z. Hu, H. Ma, F. Chen, Q. Wei, and H. Shen XRCC1 Polymorphisms and Cancer Risk: A Meta-analysis of 38 Case-Control Studies Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1810 - 1818. [Abstract] [Full Text] [PDF]

				Y.-T. Jeon, J. W. Kim, N.-H. Park, Y.-S. Song, S.-B. Kang, and H.-P. Lee DNA repair gene XRCC1 Arg399Gln polymorphism is associated with increased risk of uterine leiomyoma Hum. Reprod., June 1, 2005; 20(6): 1586 - 1589. [Abstract] [Full Text] [PDF]

				R. J. Hung, P. Brennan, F. Canzian, N. Szeszenia-Dabrowska, D. Zaridze, J. Lissowska, P. Rudnai, E. Fabianova, D. Mates, L. Foretova, et al. Large-Scale Investigation of Base Excision Repair Genetic Polymorphisms and Lung Cancer Risk in a Multicenter Study J Natl Cancer Inst, April 20, 2005; 97(8): 567 - 576. [Abstract] [Full Text] [PDF]

				M. C. Stern, K. D. Siegmund, R. Corral, and R. W. Haile XRCC1 and XRCC3 Polymorphisms and Their Role as Effect Modifiers of Unsaturated Fatty Acids and Antioxidant Intake on Colorectal Adenomas Risk Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 609 - 615. [Abstract] [Full Text] [PDF]

				J. Shen, M. D. Gammon, M. B. Terry, L. Wang, Q. Wang, F. Zhang, S. L. Teitelbaum, S. M. Eng, S. K. Sagiv, M. M. Gaudet, et al. Polymorphisms in XRCC1 Modify the Association between Polycyclic Aromatic Hydrocarbon-DNA Adducts, Cigarette Smoking, Dietary Antioxidants, and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 336 - 342. [Abstract] [Full Text] [PDF]

				G. D. Kirk, P. C. Turner, Y. Gong, O. A. Lesi, M. Mendy, J. J. Goedert, A. J. Hall, H. Whittle, P. Hainaut, R. Montesano, et al. Hepatocellular Carcinoma and Polymorphisms in Carcinogen-Metabolizing and DNA Repair Enzymes in a Population with Aflatoxin Exposure and Hepatitis B Virus Endemicity Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 373 - 379. [Abstract] [Full Text] [PDF]