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Epidemiology and Prevention |
Departments of 1 Environmental Sciences and Engineering and 2 Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina and 3 Department of Biochemistry, School of Medicine, Iwate Medical University, Iwate, Japan
Requests for reprints: Jun Nakamura, Department of Environmental Sciences and Engineering, University of North Carolina, CB 7431, Chapel Hill, NC 27599. Phone: 919-966-6140; Fax: 919-966-6123; E-mail: ynakamur{at}email.unc.edu.
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Introduction |
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X-ray cross-complementing gene 1 (XRCC1) acts as a scaffolding protein for the base excision repair (BER) and single-strand break repair (SSBR; refs. 11, 12). These overlapping pathways participate in the constitutive response to endogenous mutagens and exogenous exposures, including tobacco smoke. Specifically, XRCC1-mediated pathways repair damage to DNA bases, from oxidation or covalent binding of nonbulky electrophiles, and to the deoxyribose phosphate backbone. Quick resolution of this genetic damage is imperative because repair intermediates, such as abasic sites and SSB, are generally more genotoxic and cytotoxic than the initial lesion (13). Three common polymorphisms within the XRCC1 gene have been identified at codon 194, 280, and 399 (Arg194Trp, Arg280His, and Arg399Gln; ref. 14). These nonconservative amino acid changes may alter XRCC1 function. This change in protein biochemistry leads to the supposition that variant alleles may diminish repair kinetics, thereby influencing susceptibility to adverse health effects, including cancer (15).
Laboratory experiments and epidemiologic studies have failed to reach a consensus regarding the functional effects of XRCC1 polymorphisms (reviewed in ref. 16). Some laboratory investigations of XRCC1 codon 399 Gln functionality in human cells suggested that this polymorphism is associated with increased levels of DNA damage after exposure to various mutagens (17–19). Other reports offered conflicting evidence, suggesting that the 399Gln polymorphism has no adverse effect on DNA repair (20–22). The 194Trp variant protein does not seem to negatively alter the DNA repair capacity of human cells (18, 20). Functional studies using lymphocytes suggested that the 280His polymorphism diminishes genomic stability (20, 21).
In the present study, we further characterized and confirmed the ability of isogenic mammalian cells transfected with human XRCC1 cDNA to amend SSB caused by genotoxic stress. We directly assessed the functionality of the 280His and 399Gln variant proteins through their expression within EM9 cells, a theoretical XRCC1 knockout model (reviewed in ref. 23), and comparison with repair-proficient cells. The choice of chemicals for exposure, hydrogen peroxide (H2O2) and methyl methanesulfonate (MMS), qualitatively mimics some of the genotoxic events resulting from tobacco smoke exposure (i.e., DNA oxidation and purine alkylation by N-nitrosamines). As a result, we could infer how BER and SSBR capacity in humans would be affected by XRCC1 variants after exposure to tobacco smoke. Additionally, exposure to the topoisomerase I inhibitor camptothecin allowed for the novel functional evaluation of XRCC1 variants within tyrosyl DNA phoshodiesterase 1 (TDP1)–mediated pathways (24, 25). We then applied our observations to a population-based, case-control study to evaluate the hypothesis that the XRCC1 280His allele increases the risk of breast cancer from exposure to tobacco smoke. We found that combining the use of transgenic cells and a novel screening assay for DNA repair capacity with a traditional epidemiologic approach has proven to be an effective union for providing an increased understanding of gene-environment interactions.
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Materials and Methods |
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Chemicals. Unless noted, all chemicals used for cell exposures and the NAD(P)H assay were purchased from Sigma. MMS was obtained from Aldrich (Milwaukee, WI). Dosing and control solutions of chemicals were prepared with 1x PBS (pH 7.4; Invitrogen, Grand Island, NY).
Chemical exposures and NAD(P)H assay. Exposed cells were analyzed for an imbalance of SSBR by noninvasively monitoring intracellular NAD(P)H levels using a colorimetric assay (27) with modification. Briefly, before chemical exposures, cells were seeded onto a 96-well plate (5 x 103/50 µL/well) in DMEM/F-12 (Invitrogen) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin (Invitrogen) for an overnight incubation. For continuous exposures (i.e., MMS and camptothecin), each well has been adjusted to a volume of 110 µL with complete medium, dye, and test chemical. For H2O2 exposures, cells were exposed to H2O2 for 30 minutes at 37°C after replenishment with 50 µL serumless DMEM/F-12. To quench the oxidation reactions, DMEM/F-12 containing 20% FBS, catalase (18 units/mL), and dye were added to each well to give a final volume of 110 µL.
NAD(P)H levels were then monitored as described previously (27). Statistical evaluation of functional assay data was preformed using SAS version 9.1 (SAS Institute, Cary, NC). Due to the approximate negative exponential decay with increasing dose, NAD(P)H values were log transformed for multiple linear regression. For each chemical exposure, two-sided t tests were done comparing the regression coefficients for the wild-type response and the regression coefficient of each of the other cell lines to determine statistical significance with an 
level of 0.05.
Carolina Breast Cancer Study. The Carolina Breast Cancer Study (CBCS) is a population-based, case-control study of invasive and in situ breast cancer conducted in 24 counties of central and eastern North Carolina (28). Incident cases were identified using a Rapid Case Ascertainment System in cooperation with the North Carolina Central Cancer Registry. Controls were selected from Division of Motor Vehicles (women <65 years old) and U.S. Health Care Financing Administration lists (women 
65 years old). In-person interviews were conducted to obtain blood samples and information on potential breast cancer risk factors (28, 29).
Cases of invasive breast cancer were enrolled in two phases (phase 1: 1993-1996, phase 2: 1996-2001) with oversampling of African American and younger women (30). Controls were frequency matched to cases based on age and race (±5 years) using randomized recruitment (31). Cases of in situ breast cancer were enrolled between 1996 and 2001 and included women with ductal carcinoma in situ (DCIS) and DCIS with microinvasion to a depth of 2 mm. All cases of in situ breast cancer were eligible, with no oversampling according to age or race. Controls were frequency matched to in situ cases based on age (±5 years) and race. Race was classified according to self-report. Less than 2% of participants reported Native American or other race and were classified as White.
A total of 1,803 cases (787 African Americans and 1,016 Whites) and 1,564 controls (718 African Americans and 846 Whites) were enrolled in the invasive study, and a total of 508 cases (107 African Americans and 401 Whites) and 458 controls (70 African Americans and 388 Whites) were enrolled in the in situ study. Contact and cooperation rates for the CBCS and characteristics of cases and controls have been published previously (30). Response rates for blood draws and obtaining DNA were 90% for cases and 90% for controls. DNA samples were available for a total of 2,077 cases (786 African Americans and 1,281 Whites) and 1,818 controls (681 African Americans and 1,137 Whites). Odds ratios (OR) for breast cancer risk factors did not differ significantly between persons who gave DNA and those who did not (data not shown). XRCC1 codon 194 and 399 results for part of phase 1 of the CBCS were published previously (6). The present results combine genotypes from the entire CBCS (phases 1 and 2 and in situ studies). Results did not differ for African Americans and Whites or for invasive and in situ disease, so results are combined to increase precision.
Genotype analysis. DNA was extracted from peripheral blood lymphocytes by standard methods using an automated ABI-DNA extractor (Nuclei Acid Purification System, Applied Biosystems, Foster City, CA) in the University of North Carolina Specialized Program of Research Excellence (SPORE) Tissue Procurement Facility. Genotyping was conducted using the ABI 7700 Sequence Detection System or "Taqman" assay (Applied Biosystems). The following loci were genotyped: XRCC1 codon 194 (rs 1799782), 280 (rs 25489), and 399 (rs 25487). Primer and probe sequences as well as annealing temperatures for each genotyping assay are listed in Supplementary Table. Probes were labeled on the 5' end with either FAM or VIC (Applied Biosystems). Probes were labeled on the 3' end with the quencher dye 6-carboxy-N, N, N', N'-tetramethylrhodamine.
PCR reactions were done in 15 µL reaction volumes. Reactions contained 0.7x Universal Master Mix (Applied Biosystems), 200 nmol/L of each allele-specific probe, 900 nmol/L of each primer, and 15 ng genomic DNA. After reactions, tubes were set up and amplification was done using a Perkin-Elmer GenAmp 9700 thermocycler (Perkin-Elmer, Wellesley, MA). Reaction tubes were placed into the thermocycler after the temperature reached 50°C. PCRs were carried out using the following conditions: 50°C for 2 minutes (AmpErase UNG Activation), 95°C for 10 minutes (AmpliTaq Gold Activation), and 40 cycles of 92°C for 15 seconds (denature) and the temperature listed in Supplementary Table for 1 minute (anneal/extend). Samples that failed to amplify were repeated. Those samples that failed to amplify on the second run were scored as missing. Missing genotypes for each loci were as follows: XRCC1 codon 194 (22 cases and 1 control), 280 (41 cases and 8 controls), and 399 (72 cases and 20 controls). A 10% random sample of genotypes were repeated for each locus, and results were identical to the initial analysis. For each genotyping assay, DNA samples from the Coriell Tissue Repository (Coriell Institute for Medical Research, Camden, NJ) that have been sequenced previously at the National Cancer Institute (NCI; http://www.nci.snp500.gov) were used as positive controls.
Statistical methods. Departures from Hardy-Weinberg equilibrium were evaluated by calculating expected genotype frequencies among controls based on observed allele frequencies and comparing the expected frequencies to observed genotype frequencies using 
2 tests. Differences between allele or genotype frequencies in cases and controls were estimated using 2 tests or Fisher's exact tests when expected counts were <5. Tests for statistical significance were two-sided with an level of 0.05. SAS Genetics version 8.2 (SAS Institute) was used to estimate XRCC1 codon 194 + 280 + 399 haplotype frequencies and to compare haplotype frequencies in cases and controls. Haplotype estimates from SAS Genetics are based on the EM algorithm (32). Lewontin's D' value, an estimate of the extent of linkage disequilibrium, was calculated using SAS Genetics for pair-wise comparisons of XRCC1 codon 194 and 280 and codon 280 and 399.
Unconditional logistic regression was used to calculate ORs for breast cancer and 95% confidence intervals (95% CI). PROC GENMOD in SAS version 8.2 (SAS Institute) was used to incorporate offsets derived from sampling probabilities used to identify eligible participants (31) and to adjust for race (African American and White) and age (as an 11-level ordinal variable that reflected 5-year age categories).
Analysis of smoking effects used a common reference group of women who were not exposed to active or passive smoking. Ever-active smokers were defined as women who smoked at least 100 cigarettes in their lifetime. Exposure to passive smoking was defined as living with a smoker after age 18 (ETS after 18). Women who smoked on the reference date (date of diagnosis for cases or date of selection for controls) were classified as current smokers, whereas those women who no longer smoked on the reference date were designated former smokers. Women were asked about the amount of cigarettes smoked (packs per day) and the duration of smoking (the total number of years the participant smoked regularly). Information on duration of smoking was obtained by asking participants, "Keeping in mind that you may have stopped and started several times, overall how many years have you smoked regularly?" Dose of smoking was obtained by asking, "On average, how many cigarettes did you smoke per day?" ORs for smoking dose and duration were calculated separately for current smokers and former smokers, and these groups were combined in the present analysis because positive associations were observed in both groups. Information regarding dose and duration of smoking was missing for three White cases. Multivariable logistic regression was used to adjust for potential confounding factors. Confounding was evaluated by determining whether adding a variable to a model resulted in a change in the ß coefficient of at least 10% for the exposure of interest. The following confounding variables were identified for the association of smoking and breast cancer: age at menarche (<12, 12 years), a composite term for age at first full-term pregnancy and parity (nulliparous, parity = 1 and age at first full-term pregnancy <26, parity = 1 and age at first full-term pregnancy 26, parity 2 and age at first full-term pregnancy <26, parity 2 and age at first full-term pregnancy 26), family history of breast cancer (yes/no for first-degree relative), and alcohol consumption (never/ever). ORs for XRCC1 genotypes and breast cancer were unchanged after adjusting for smoking and the other covariates listed and thus are presented adjusted for offsets (sampling probabilities), age and race only. Participants with missing values for any of the variables in a regression model were omitted from the analysis.
Stratified analyses were used to investigate modification of ORs for smoking and breast cancer by XRCC1 genotype. ORs for smoking were calculated according to each XRCC1 genotype separately. In addition, we wished to estimate effects for XRCC1 codon 194 and 399 separately, while ignoring codon 280 genotype, to compare our results with previous epidemiologic studies of XRCC1. Tests for trend for smoking dose and duration were conducted by calculating Ps for the ß coefficient in logistic regression models with smoking dose or duration coded as an ordinal variable. Results were similar for African American and White participants; therefore, only combined results are shown. The term "Any genotype" refers to one or more copies of the less common allele (e.g., XRCC1 codon 194). "Any Trp" refers to "Arg/Trp or Trp/Trp genotype."
Interactions between XRCC1 genotypes and smoking on a multiplicative scale were evaluated using likelihood ratio tests (LRT). An value of 0.20 was used for statistical significance to account for the lower power of the test (33).
Interactions on an additive scale were assessed by estimating independent and joint effects for XRCC1 genotypes and smoking using a single reference of never-smokers and low-risk XRCC1 genotype. Departures from additive effects were assessed using interaction contrast ratios (ICR). ICRs greater than zero imply greater than additive effects or synergy (34).
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To determine the influence of XRCC1 polymorphisms on interactions with proteins involved in a TDP1-mediated pathway, we exposed the transfected cell lines to the topoisomerase I inhibitor camptothecin (Fig. 1C). After 4 hours of continuous exposure, the EM9-WT, EM9-399Gln, and EM9-280His cell lines showed <10% decreases in NAD(P)H relative to controls, indicating no influences of XRCC1 genotypes on this repair pathway. The repair-deficient EM9-V cells showed a 25% decrease in NAD(P)H at the highest dose level.
Because data indicated that the XRCC1 280His variant was a functionally detrimental polymorphism, we evaluated XRCC1 genotype and smoking history data from the CBCS. Genotype frequencies, allelic frequencies, and ORs for breast cancer for XRCC1 codon 194, 280, and 399 genotypes are presented in Table 1. Allele and genotype frequencies were similar in African Americans and Whites and between cases and controls within each racial group with respect to XRCC1 codon 194 and 280. The frequency of the codon 399 Gln variant was greater in White controls (q = 0.35) than African American controls (q = 0.14). Genotypes for each XRCC1 locus were observed to be in Hardy-Weinberg equilibrium among African American cases, African American controls, White cases, and White controls (data not shown). For each locus, comparisons between the Arg/Arg genotype and the variant genotypes did not yield any statistically significant increases in ORs for breast cancer. Haplotype frequencies for XRCC1 in African American and Whites are presented in Table 2. Haplotype frequencies did not differ between cases and controls for either racial group. The 194Arg + 280Arg + 399Arg haplotype was the most common in both African Americans and Whites. The 280His allele was in strong linkage disequilibrium with 194Arg (D' = 1.0) and 399Arg (D' = 1.0) in both racial groups. Results for non–African Americans were not affected by exclusion of the 2% of participants who were non-White.
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Discussion |
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Here, we showed that the XRCC1 280His variant attenuated the DNA repair capacity of transgenic cells after exposure to oxidative stress. Additionally, our functional evaluation substantiated a previous observation (26) that the 280His variant hinders the efficient repair of DNA damage from alkylative stress. These observations were evident from greater NAD(P)H depletions caused by poly(ADP-ribose) polymerase-1 overactivation in response to the accumulation of SSB. Relative to the EM9-WT and EM9-399Gln cells, NAD(P)H depletions in EM9-280His cells were greater after exposure to H2O2 or MMS (Fig. 1A and B), suggesting an inability to efficiently amend DNA damage. Because NAD(P)H depletion in EM9-399Gln cells was similar to that in EM9-WT cells, it seems that the 399Gln variant protein does not negatively affect XRCC1-mediated repair. When exposed to the topoisomerase I inhibitor camptothecin, all cell lines, excluding the repair-deficient EM9-V line, had levels of NAD(P)H near 100% of control levels (Fig. 1C). These data suggest that the functionality of XRCC1 polymorphisms is relevant only to the removal of damaged bases or frank SSB and not abortive topoisomerase I activity.
Prior functional studies in human and rodent cell models support our observations regarding the XRCC1 399Gln and 280His variants. Human cells with the 399Gln allele were not sensitive to bleomycin-induced DNA damage compared with lymphocytes with the codon 399 Arg/Arg genotype (20). Expression of the 399Gln variant protein in an EM9 background restored DNA repair capacity and cell survival to a level similar to that of EM9-WT cells after exposure to MMS (38). Lymphocytes from individuals carrying the 280His allele showed increased genetic damage from bleomycin exposure relative to 280 Arg/Arg homozygotes (20). The 280His polymorphism was also associated with increased chromosomal aberrations in lymphocytes (21). Although not assessed in this study, prior investigations of the Arg194Trp variant protein in human cells have shown that this protein does not alter DNA repair capacity from bleomycin exposure (20). Additionally, after MMS exposure, EM9 cell lines expressing the 194Trp variant protein (EM9-194Trp) as well as EM9-WT and EM9-399Gln cells responded similar to repair-proficient AA8 cells in terms of survival (26).
A decrease in DNA repair capacity precipitated by the 280His variant seems to be biologically plausible. The 280 codon of the XRCC1 polypeptide lies within the AP endonuclease (APE)–binding domain (11). The nonsynonymous Arg280His polymorphism causes the replacement of arginine with histidine, which changes the amino acid sequence of XRCC1. This change in protein biochemistry could potentially alter XRCC1 structure and its ability to interact with APE. The 280His protein only seems to have a negative effect during BER or SSBR induced by either base damage or DNA oxidation, processes that both involve APE. During the repair of SSB formed by camptothecin exposure, a process independent of APE activity, EM9-280His cells show a phenotypic response similar to that of EM9-WT cells (Fig. 1C). Additionally, when expressed in EM9 cells, the 280His variant protein failed to localize to DNA damage foci with the same efficiency as the wild-type protein (26).
The association of XRCC1 genotypes and breast cancer has been examined in 13 epidemiologic studies (5, 40–51) in addition to a previous report from phase 1 of the CBCS (6). Only the CBCS included significant numbers of African Americans. For codon 194, positive associations were observed for Trp-containing genotypes in four studies (40, 46, 48, 49), an inverse association in one study (47), and no association in five studies (5, 42, 44, 50, 51). Increased risk for codon 280 His-containing genotypes was observed in one study (5) and no association in three studies (40, 43, 46). For codon 399, positive associations were observed for Gln-containing genotypes in three studies (40, 44, 46) and no association in nine studies (5, 41–43, 45, 48–51). A meta-analysis by Hung et al. (16) combined results from 10 breast cancer studies (5, 6, 44–51). Summary ORs were close to the null for codon 194 and 399 genotypes and breast cancer (16). Three epidemiologic studies of breast cancer analyzed XRCC1 haplotypes (5, 47, 52), and results were consistent with the presence of the less common codon 280 His allele solely on the codon 194 Arg + codon 399 Arg chromosomal background.
Four breast cancer studies examined interactions between XRCC1 genotypes and smoking (41–43, 47). Han et al. (47) reported a trend of increasing breast cancer risk with increasing duration of smoking among study participants with the codon 194 Arg/Arg genotype but not among codon 194 Trp carriers, consistent with the results of our study. For codon 399, Metsola et al. (43) and Shen et al. (42) reported interactions between Gln-containing genotypes and smoking, but no interactions were observed by Figueiredo et al. (41) and Han et al. (47). Metsola et al. (43) reported a stronger association for codon 280 His-containing genotypes and breast cancer among heavy smokers. A meta-analysis by Hung et al. (16) of tobacco-related cancers (lung, upper aerodigestive tract, bladder, stomach, liver, pancreas, and myeloid leukemia) found a protective effect for codon 194 Trp-containing genotypes among ever-smokers. Codon 399 Gln-containing genotypes were associated with increased risk of tobacco-related cancers among light smokers but a decreased risk among heavy smokers (16). These results are compatible with our observation of a stronger association between breast cancer and increased duration and dose of smoking among study participants with codon 194 Arg/Arg and codon 399 Arg/Arg genotypes. Hung et al. (16) reported a summary OR close to the null for codon 280 His-containing genotypes and tobacco-related cancers, but the data were too sparse to stratify on smoking history. For results of additional epidemiologic studies of XRCC1, see Hung et al. (16) and Goode et al. (3).
Evaluating gene-environment interactions using a transgenic cell system as a screen for functional polymorphisms has advantages over human cell-based functional assays. The use of isogenic EM9 cells expressing human XRCC1 protein allowed for direct functional characterization of variant proteins without confounding by other genetic modifiers. Additionally, we found this Chinese hamster ovary model to be preferable over genetically matched lymphocyte cell lines from cases and controls carrying the 280His allele, because human lines exhibit different rates of growth (data not shown), a potential source of confounding, and a concern for assay variability. The use of a sensitive, real-time NAD(P)H assay to assess BER/SSBR capacity afforded us the flexibility to reproducibly test several exposure scenarios in a relatively short amount of time. The stable transfection of plasmids harboring human cDNA of other polymorphic genes into isogenic knockout cells would extend the applicability of this approach. Our combined study design provides a robust examination of the biological significance for XRCC1 polymorphisms. The precise functional evaluation of XRCC1 polymorphisms through a laboratory study lends biological plausibility to the findings from an epidemiologic study of breast cancer susceptibility. The strategy could prove useful for clarifying the biological significance of other genetic polymorphisms in DNA repair genes, particularly those with low allelic frequencies.
In summary, we further characterized the functionality of the XRCC1 280His polymorphism and used these observations to clarify the relationship between this allele, breast cancer, and smoking. The XRCC1 codon 280 His allele is in linkage disequilibrium with the more common variants for two other XRCC1 polymorphisms at codon 194 and 399. Functional and epidemiologic data suggest that the XRCC1 codon 280 His allele may be more important than codon 194 or 399 alleles with respect to smoking and breast cancer. Haplotype analyses, particularly using anonymous tagSNPs, may prove useful for identifying genetic heterogeneity when functional alleles are unknown. However, identification of functionally relevant alleles within defined haplotypes, as presented here, will also contribute important information for understanding gene-environment and gene-gene interactions.
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Acknowledgments |
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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.
We thank Allison Eaton, Kendra Worley, Jon Player, Allan Rene de Cotret (University of North Carolina High-Throughput Genotyping Core Laboratory), and Daynise Skeen (University of North Carolina SPORE Tissue Procurement Facility) for technical assistance and Dr. Michael Symons for statistical consultation with the functional assay.
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Footnotes |
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Received 9/21/05. Revised 12/21/05. Accepted 12/29/05.
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), 399Gln (EM9-399Gln; 
), or 280His (EM9-280His; 
) polymorphisms or an empty vector (EM9-V; 
), were exposed (A) for 30 minutes to H2O2, (B) continuously to MMS, or (C) continuously to camptothecin. NAD(P)H levels were monitored in real-time for 4 hours during (MMS and camptothecin) or after (H2O2) exposure. NAD(P)H data for exposed wells were percentage relative to NAD(P)H levels (100%) in corresponding control wells of the same cell line dosed with PBS. Chemical exposures were conducted in triplicate and repeated on different days. Points, mean; bars, SD. *, P < 0.05; **, P < 0.01, significant difference from wild-type line.