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XRCC1 Polymorphisms and Cancer Risk: A Meta-analysis of 38 Case-Control Studies

¹ Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, Nanjing, China and ² Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Hongbing Shen, Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, 140 Hanzhong Road, 210029 Nanjing, China. Phone: 86-25-868-62747; Fax: 86-25-865-27613. E-mail: hbshen{at}njmu.edu.cn

	Abstract

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Several potential functional polymorphisms (Arg¹⁹⁴Trp, Arg²⁸⁰His, Arg³⁹⁹Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg¹⁹⁴Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg²⁸⁰His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg³⁹⁹Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg¹⁹⁴Trp, Arg²⁸⁰His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.

	Introduction

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Human cancer can be initiated by DNA damage caused by UV, ionizing radiation, and environmental chemical agents. To safeguard the integrity of genome, humans have developed a set of complex DNA repair systems. Among the five main DNA maintenance mechanisms operating in mammals, base excision repair is the primary guardian against damage that results from cellular metabolism, including reactive oxygen species, methylation, deamination, and hydroxylation. Therefore, base excision repair is a universal event in the cells and is relevant for preventing mutagenesis.

X-ray repair cross complementing group 1 (XRCC1), one of the >20 genes that participate in base excision repair pathway, encodes a scaffolding protein that functions in the repair of single-strand breaks, the most common lesions in cellular DNA (1). Both biological and biochemical evidence indicates a direct role for XRCC1 in base excision repair because it interacts with a complex of DNA repair proteins, including poly(ADP-ribose) polymerase, DNA ligase 3, and DNA polymerase-ß (1-3). There are a total of eight nonsynonymous coding single nucleotide polymorphisms in XRCC1, three of which are common (variant allele frequency > 0.05) and lead to amino acid substitutions in XRCC1 at codon 194 (exon 6, base C to T, amino acid Arg to Trp), codon 280 (exon 9, base G to A, amino acid Arg to His), and codon 399 (exon 10, base G to A, amino acid Arg to Gln) (http://egp.gs.washington.edu). Because the Arg³⁹⁹Gln polymorphism is located in the region of the BRCT-I interaction domain of XRCC1 within a poly(ADP-ribose) polymerase binding region, this polymorphism has been extensively investigated both in its function and in its association with cancer risk. The presence of the variant Gln³⁹⁹ allele has been shown to be associated with measurable reduced DNA repair capacity as assessed by the persistence of DNA adducts (4-6), elevated levels of sister chromatid exchanges (5, 7), increased RBC glycophorin A (4), p53 mutations (8), and prolonged cell cycle delay (9). However, Taylor et al. (10) reported that whereas BRCT-I is critical for XRCC1-dependent SSBR for maintenance of genetic integrity, the Arg³⁹⁹Gln polymorphism in BRCT-I does not have a significant impact on this function and negative findings were also obtained from other individual studies (11-13). A large number of molecular epidemiologic studies have been conducted to evaluate the role of the Arg³⁹⁹Gln polymorphism on cancer risk; however, the results remain conflicting rather than conclusive (6, 14-49).

Both the XRCC1 Arg¹⁹⁴Trp and Arg²⁸⁰His variants occur in the newly identified proliferating cell nuclear antigen binding region (50), which consists of polar Pro-, Ser-, and Arg/Lys-rich regions. The transition from a positively charged Arg to a hydrophobic Trp within the conserved region may alter XRCC1 function. Recently, Wang et al. (51) reported that individuals with the variant Trp¹⁹⁴ allele had fewer bleomycinor benzo(a)pyrene diol epoxide–induced chromosomal breaks than those with wild-type genotype; however, others did not find a significant association of Arg¹⁹⁴Trp with altered levels of DNA adducts (4) and G₂ cell cycle delay (9). Molecular epidemiologic studies on the association between this polymorphism and cancer risk also presented contradicting results (14-17, 19-23, 26-29, 31-34, 39-43, 49). To date, there are relatively few studies conducted to examine the association between Arg²⁸⁰His variant and cancer risk (19, 20, 22, 31, 33, 35, 40, 52) and only one study evaluated the association of Arg²⁸⁰His and altered DNA adducts (4). Because a single study may have been underpowered to detect the effect of low-penetrance genes and particularly their dose-response relationships, a quantitative synthesis to accumulate data from different studies may provide evidence on the association of genetic polymorphisms with cancer risk. In this meta-analysis, we aimed to obtain summary risk estimates for the above-mentioned three nonsynonymous coding single nucleotide polymorphisms of XRCC1 associated with cancer risk, as well as to quantify the potential between-study heterogeneity.

	Materials and Methods

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Identification and Eligibility of Relevant Studies
We have attempted to include all the case-control association studies of cancer with genotyping data for at least one of the three polymorphisms, Arg³⁹⁹Gln, Arg¹⁹⁴Trp, and Arg²⁸⁰His. Eligible studies were identified by searching the electronic literature MEDLINE for relevant reports (last search update July 15, 2004, using the search terms "XRCC1 and cancer"). Additional studies were identified by a hand search of references of original studies or review articles on this topic and by personal contact with the authors if necessary.

A total of 43 published studies examined the relationship between XRCC1 polymorphisms and cancer risk, three of which were excluded because they did not have an appropriate case-control design (53) or they did not present detailed genotyping information for the three polymorphisms (54, 55). Another three studies were excluded because they investigated the same or a subset population of reported articles (56-58). Hence, the data for this analysis were available from 38 case-control studies, including 11,542 cancer cases and 13,694 controls for Arg³⁹⁹Gln (from 37 studies), 4,933 cancer cases and 6,775 controls for Arg¹⁹⁴Trp (from 22 studies), and 1,688 cancer cases and 2,129 controls for Arg²⁸⁰His (from 8 studies).

Data Extraction
Two investigators independently extracted data and reached a consensus on all of the items. The following information was sought from each article: author, journal and year of publication, country of origin, selection and characteristics of cancer cases and controls, demographics, ethnicity, and genotyping information. For studies including subjects of different ethnicities, data were extracted separately and categorized as European, African, and Asian. However, if the authors did not clearly state the ethnic information or we could not separate them according to genotypes, the term "mixed ethnicity" was used (Table 1).

In addition to comparisons for total subjects, studies were categorized into different subgroup analyses according to the ethnicity and tumor type (if the tumor type contains less than three individual studies, it was categorized into the "other cancer" group). For each subgroup, we estimated the between-study heterogeneity across the eligible comparisons using the ²-based Q test (59) and the heterogeneity was considered significant for P < 0.05. Values from single studies were combined using models of both fixed effects (Mantel-Haenszel) and random effects (DerSimonian and Laird; ref. 60). Random effects incorporate an estimate of the between-study variance and tend to provide wider confidence intervals when the results of the constituent studies differ among themselves. In the absence of between-study heterogeneity, the two methods provide identical results. We also did cumulative meta-analysis to evaluate whether the summary OR for the allele contrasts changed over time as more data accumulated (61). Inverted funnel plots and the Egger's test were used to provide diagnosis of publication bias (linear regression analysis; ref. 62).

All analyses were done in Statistical Analysis System software (v.8.0; SAS Institute, Cary, NC) and Review Manage (v.4.2; Oxford, England). All the P values were two-sided.

	Results

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Meta-analyses Databases
We established a database according to the extracted information from each article. Table 1 lists the cancer type of the study, ethnicity of the population, and the number of cases and controls for each XRCC1 polymorphisms. There are total 37 case-control studies concerning Arg³⁹⁹Gln polymorphism, 22 for Arg¹⁹⁴Trp, and 8 for Arg²⁸⁰His. All studies indicated that the distribution of genotypes in the controls was consistent with Hardy-Weinberg equilibrium [goodness of fit ² test, degree of freedom (df) = 1], except for three studies for Arg³⁹⁹Gln (21, 27, 44), one study for Arg¹⁹⁴Trp (32), and one study for Arg²⁸⁰His (20). However, only 27% of the studies for Arg³⁹⁹Gln, 14% for Arg¹⁹⁴Trp, and none for Arg²⁸⁰His had a statistical power >80% based on the assumption that the cancer risk (OR) associated with the variant genotypes was >1.5. According to quality control on genotyping, three studies obtained DNA from surgically resected "normal" tissues adjacent to the tumor instead of peripheral blood (18, 28, 52). A classic PCR-RFLP assay was done in 81% of the studies, 41% randomly repeated a portion of samples while genotyping, and 22% used other genotyping assay to validate the data. Only 19% of the studies described use of blindness of the case-control status of DNA samples while genotyping.

Quantitative Synthesis
XRCC1 Arg³⁹⁹Gln. The eligible studies included 11,542 cancer patients and 13,694 control subjects. There were significant differences in terms of the variant Gln³⁹⁹ allele frequency between the three major ethnicities [European, 34.7%; 95% confidence interval (95% CI), 33.8-35.6; Asian, 26.5%; 95% CI, 25.6-27.4; African, 15.5%; 95% CI, 13.5-17.7; P < 0.0001; Fig. 1]. Figure 2 shows the cancer risks (ORs) associated with the XRCC1 Gln/Gln genotype compared with the Arg/Arg genotype. Overall, individuals carrying the XRCC1 Gln/Gln genotype did not have elevated cancer risk compared with the individuals with the Arg/Arg genotype (OR, 1.01; 95% CI, 0.90-1.14; P = 0.02 for heterogeneity), and this negative associations were also observed in subgroups stratified by cancer type and ethnicity (Fig. 2). Similarly, no association with cancer risk was found, neither in the recessive (Gln/Gln versus Arg/Gln + Arg/Arg: OR, 1.03; 95% CI, 0.92-1.15, P = 0.02 for heterogeneity) nor in the dominant model of the Gln³⁹⁹ allele (Gln/Gln + Arg/Gln versus Arg/Arg: OR, 1.00; 95% CI, 0.95-1.05; Table 2). In the stratified analyses, however, significantly increased risks were found in the Asian subjects (OR, 1.18; 95% CI, 1.00-1.39) in the recessive model and among the African subjects (OR, 1.45; 95% CI, 1.13-1.88) in the dominant model (Table 2).

View larger version (15K): [in this window] [in a new window]   Figure 1. Allele frequencies and their 95% CIs of the XRCC1 codon 399 and 194 polymorphisms among control subjects by different ethnicity. Each data point represents a separate study for the indicated association.

View larger version (34K): [in this window] [in a new window]   Figure 2. ORs (log scale) of cancer associated with XRCC1 codon 399 for the Gln/Gln genotype compared with the Arg/Arg genotype. For each study, the estimate of OR and its 95% CI is plotted with a box and a horizontal line. , pooled OR and its 95% CI.

View larger version (38K): [in this window] [in a new window]   Figure 3. ORs (log scale) of cancer associated with XRCC1 codon 194 for the Trp/Trp and Arg/Trp genotypes compared with the Arg/Arg genotype. For each study, the estimate of OR and its 95% CI is plotted with a box and a horizontal line. , pooled OR and its 95% CI.

View larger version (14K): [in this window] [in a new window]   Figure 4. ORs (log scale) of cancer associated with XRCC1 codon 280 for the His/His and Arg/His genotypes compared with the Arg/Arg genotype. For each study, the estimate of OR and its 95% CI is plotted with a box and a horizontal line. , pooled OR and its 95% CI.

	Bias Diagnostics

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XRCC1 Arg³⁹⁹Gln. The magnitude of the summary ORs had been fluctuating at around 1 in the past years (in random effect model, summary OR for Gln/Gln versus Arg/Arg: 1.03 at the end of 2001, 0.98 at the end of 2002, 1.04 at the end of 2003, and 1.03 till now). In the funnel plot analysis of publication bias (contrast of homozygous genotype plotted against the precision), the shape of the funnel plot seems asymmetrical, suggesting that the larger estimate of the association belongs to the smaller study, whereas the larger study shows little effect (Fig. 5). Furthermore, an Egger's test was used to provide statistical evidence for funnel plot symmetry (62). In the linear regression analysis, the intercept value provides a measure of asymmetry—the larger its deviation from zero, the more pronounced the asymmetry. We observed the intercept values of 1.57, which significantly deviated from zero (t = 3.85, P < 0.001).

View larger version (10K): [in this window] [in a new window]   Figure 5. Funnel plot analysis to detect publication bias. Each point represents a separate study for the indicated association. For each study, the OR is plotted on a logarithmic scale against the precision (the reciprocal of the SE). If bias is absent, small studies will have ORs that are widely scattered but still centered around the OR estimates provided by large, more precise studies.

XRCC1 Arg²⁸⁰His. In cumulative meta-analysis and recursive cumulative meta-analysis, the summary ORs changed considerably in the year 2004 with a sharp reduction of the postulated effect (summary ORs for His/His + Arg/His versus Arg/Arg: 1.36 at the end of 2001, 1.38 at the end of 2002, 1.40 at the end of 2003, and 1.19 till now). This change mainly resulted from the study of esophageal cancer by Hao et al. (52), which is the only study that presented a protective effect of the variant genotypes. Furthermore, the funnel plot and Egger's test revealed that publication bias might have influenced the estimates (intercept values 2.15, P = 0.002).

	Discussion

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This meta-analysis, including a total of 11,957 cancer cases and 14,174 controls from 38 case-control studies, examined the association of three well-characterized polymorphisms of the DNA repair gene XRCC1 (Arg¹⁹⁴Trp, Arg²⁸⁰His, and Arg³⁹⁹Gln) with cancer risk. There was no overall effect either in recessive or dominant modeling for the Arg³⁹⁹Gln polymorphism, and compared with the wild Arg/Arg genotype, variant Gln/Gln homozygote was not associated with overall cancer risk. For the Arg¹⁹⁴Trp, the variant genotypes (Trp/Trp + Arg/Trp), compared with the wild-type homozygote (Arg/Arg), were associated with a significantly decreased cancer risk (OR, 0.89; 95% CI, 0.81-0.98) for all tumor types without between-study heterogeneity. Similarly, we observed a fixed overall 19% increased risk of cancer for the variant genotypes (His/His + Arg/His) of the Arg²⁸⁰His polymorphism, compared with the wild homozygote (OR, 1.19; 95% CI, 1.00-1.42). However, considering the relatively small sample size and marginal statistical evidence for Arg²⁸⁰His, our result in relation to this polymorphism should always be treated as preliminary. Nevertheless, our analysis shows that even if a common variant in the functional region of a definitively meaningful gene had an effect on human disease, such as cancer, it may play only a small role in the disease causation, which is consistent with the characteristics of low-penetrance genes (63).

Given the multiplicity of possible comparisons and the unavoidable flexibility of choosing and defining the correlates, associations may have been detected by chance alone. Several criteria have been proposed for assessing associations between genetic polymorphisms and disease (64); the claim was that studies "ideally should have large sample sizes, small P values, report associations that make biological sense, and alleles that affect the gene product in a physiologically meaningful way." The sample size and scientific hypotheses of the study are obviously important to know the proportion of false-positive findings of meta-analysis that are attributable to constituent studies with poor study design, nondifferential misclassification errors, and selection bias from publication (65). Although considerable effort and resources have been put into testing possible associations between DNA repair gene XRCC1 polymorphisms and cancer risk, there are still serious limitations inherited from the published studies. First, selection bias could have played a role because the genotype distributions of at least one polymorphism among control subjects disobeyed the law of Hardy-Weinberg equilibrium in five studies (20, 21, 27, 32, 44). Second, demographic parameters are not well matched and are statistically adjusted in a few studies (26, 32, 36, 39, 44, 49). Third, misclassifications on disease status and genotypes may also influence the results because cases in several studies were not confirmed by pathology or other gold standard methods, and the quality control of genotyping was also not well-documented in some studies. Finally, the Egger's test revealed that there are considerable unpublished negative studies not included in this meta-analysis although they are likely to be small in terms of sample size. However, because the Trp¹⁹⁴ allele was associated with a decreased cancer risk and the unpublished studies on this polymorphism are likely to show a protective effect, the association between the Arg¹⁹⁴Trp variant and cancer risk may be slightly underestimated. To further evaluate the results derived from Egger's test, we searched the abstracts from annual meetings of AACR between 2000 and 2004 and found 24 eligible case-control studies. Among the 24 abstracts, 11 were fully or partially published and had been included in the current meta-analysis and only 2 unpublished studies were with a sample size of >300 cases. One study conducted in Finland with 483 breast cancer patients and 482 controls reported that no association between the Arg³⁹⁹Gln polymorphism and breast cancer risk (66). The other multicentric study in central and eastern Europe consisted of a large sample size (2,073 cases and 1,953 controls) showed that Arg²⁸⁰His, Arg³⁹⁹Gln did not confer an effect on lung cancer, whereas Arg¹⁹⁴Trp showed a protective effect among current smokers (OR, 0.76; 95% CI, 0.42-0.99; ref. 67). These two meeting abstracts with relatively large sample size also support the current meta-analysis that XRCC1 Arg¹⁹⁴Trp rather than Arg²⁸⁰His and Arg³⁹⁹Gln may play a role in individual susceptibility to cancers.

Several studies suggested a possible interaction between XRCC1 Arg³⁹⁹Gln and family history on breast cancer risk (48), indicating that family history, particularly in first-degree relatives, broadly represents shared genes and environmental factors, and that the weak effect of a single polymorphism on the individual's phenotype may not be measurable except in the context of these risk factors. In addition, cigarette smoking (36), alcohol consumption (35), and antioxidant vitamins intake (43) are associated with the production of free radical intermediates, including hydroxyethyl free radicals and reactive oxygen species, which are corrected in part by the involvement of XRCC1. Therefore, gene-to-environment interactions have been of great interest to evaluate the exact roles of genetic polymorphisms. However, lacking of the original data of the meta-analysis limited our further evaluation of potential gene-to-gene and gene-to-environment interactions.

The heterogeneity test revealed that there was no significant between-study heterogeneity in terms of the XRCC1 Arg¹⁹⁴Trp polymorphism for all tumor types. In addition, different tumor types also did not significantly contribute to the overall heterogeneity in relation to the Arg³⁹⁹Gln polymorphism, indicating that our current combined analyses were unbiased, regardless of tumor types. Because we did not find any significant heterogeneity in the distribution of the Arg³⁹⁹Gln genotypes by ethnicity and the study sample size, it is possible that other unmeasured characteristics in different study populations and/or inherited limitations of the recruited studies may partially contribute to the observed overall heterogeneity. Although heterogeneity among different ethnic groups was not statistically significant in our combined analysis, other population stratification factors may have played a role in the heterogeneity when the sample size of a combined analysis become sufficient large (68) and, therefore, we suggest a careful matching on ethnicity for future larger genetic association studies.

In conclusion, our current study support that XRCC1 Arg¹⁹⁴Trp polymorphism may contribute to individual susceptibility of cancers. To further evaluate gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk, a single larger study with thousands of subjects and tissue-specific biochemical and biological characterizations are required.

	Footnotes

 
Grant support: National Key Basic Research Program grants 2002CB512900 and National Natural Science Foundation grant 30371240.

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.

Received 10/28/04; revised 3/24/05; accepted 4/18/05.

	References

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1. Caldecott KW, Tucker JD, Stanker LH, Thompson LH. Characterization of the XRCC1-DNA ligase III complex in vitro and its absence from mutant hamster cells. Nucleic Acids Res 1995;23:4836–43.[Abstract/Free Full Text]
2. Dianov GL, Prasad R, Wilson SH, Bohr VA. Role of DNA polymerase ß in the excision step of long patch mammalian base excision repair. J Biol Chem 1999;274:13741–3.[Abstract/Free Full Text]
3. Thompson LH, West MG. XRCC1 keeps DNA from getting stranded. Mutat Res 2000;459:1–18.[Medline]
4. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res 1999;59:2557–61.[Abstract/Free Full Text]
5. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 2000;21:965–71.[Abstract/Free Full Text]
6. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer 2001;92:562–7.[CrossRef][Medline]
7. Lei YC, Hwang SJ, Chang CC, et al. Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. Mutat Res 2002;519:93–101.[Medline]
8. Hsieh LL, Chien HT, Chen IH, et al. The XRCC1 399Gln polymorphism and the frequency of p53 mutations in Taiwanese oral squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev 2003;12:439–43.[Abstract/Free Full Text]
9. Hu JJ, Smith TR, Miller MS, Mohrenweiser HW, Golden A, Case LD. Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis 2001;22:917–22.[Abstract/Free Full Text]
10. Taylor RM, Thistlethwaite A, Caldecott KW. Central role for the XRCC1 BRCT I domain in mammalian DNA single-strand break repair. Mol Cell Biol 2002;22:2556–63.[Abstract/Free Full Text]
11. Pastorelli R, Cerri A, Mezzetti M, Consonni E, Airoldi L. Effect of DNA repair gene polymorphisms on BPDE-DNA adducts in human lymphocytes. Int J Cancer 2002;100:9–13.[CrossRef][Medline]
12. Gao WM, Romkes M, Day RD, et al. Association of the DNA repair gene XPD Asp³¹²Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer. Carcinogenesis 2003;24:1671–6.[Abstract/Free Full Text]
13. Hou SM, Ryk C, Kannio A, et al. Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors. Environ Mol Mutagen 2003;41:37–42.[CrossRef][Medline]
14. Sturgis EM, Castillo EJ, Li L, et al. Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck. Carcinogenesis 1999;20:2125–9.[Abstract/Free Full Text]
15. Shen H, Xu Y, Qian Y, et al. Polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population. Int J Cancer 2000;88:601–6.[CrossRef][Medline]
16. Abdel-Rahman SZ, Soliman AS, Bondy ML, et al. Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt. Cancer Lett 2000;159:79–86.[CrossRef][Medline]
17. Winsey SL, Haldar NA, Marsh HP, et al. A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 2000;60:5612–6.[Abstract/Free Full Text]
18. Divine KK, Gilliland FD, Crowell RE, et al. The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung. Mutat Res 2001;461:273–8.[Medline]
19. Ratnasinghe D, Yao SX, Tangrea JA, et al. Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2001;10:119–23.[Abstract/Free Full Text]
20. Stern MC, Umbach DM, van Gils CH, Lunn RM, Taylor JA. DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 2001;10:125–31.[Abstract/Free Full Text]
21. Duell EJ, Millikan RC, Pittman GS, et al. Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomarkers Prev 2001;10:217–22.[Abstract/Free Full Text]
22. Lee JM, Lee YC, Yang SY, et al. Genetic polymorphisms of XRCC1 and risk of the esophageal cancer. Int J Cancer 2001;95:240–6.[CrossRef][Medline]
23. David-Beabes GL, London SJ. Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians. Lung Cancer 2001;34:333–9.[CrossRef][Medline]
24. Nelson HH, Kelsey KT, Mott LA, Karagas MR. The XRCC1 Arg³⁹⁹Gln polymorphism, sunburn, and non-melanoma skin cancer: evidence of gene-environment interaction. Cancer Res 2002;62:152–5.[Abstract/Free Full Text]
25. Park JY, Lee SY, Jeon HS, et al. Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 2002;11:23–7.[Abstract/Free Full Text]
26. Olshan AF, Watson MA, Weissler MC, Bell DA. XRCC1 polymorphisms and head and neck cancer. Cancer Lett 2002;178:181–6.[CrossRef][Medline]
27. Kim SU, Park SK, Yoo KY, et al. XRCC1 genetic polymorphism and breast cancer risk. Pharmacogenetics 2002;12:335–8.[CrossRef][Medline]
28. Xing D, Qi J, Miao X, Lu W, Tan W, Lin D. Polymorphisms of DNA repair genes XRCC1 and XPD and their associations with risk of esophageal squamous cell carcinoma in a Chinese population. Int J Cancer 2002;100:600–5.[CrossRef][Medline]
29. Chen S, Tang D, Xue K, et al. DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population. Carcinogenesis 2002;23:1321–5.[Abstract/Free Full Text]
30. Duell EJ, Holly EA, Bracci PM, Wiencke JK, Kelsey KT. A population-based study of the Arg³⁹⁹Gln polymorphism in X-ray repair cross-complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma. Cancer Res 2002;62:4630–6.[Abstract/Free Full Text]
31. Lee SG, Kim B, Choi J, Kim C, Lee I, Song K. Genetic polymorphisms of XRCC1 and risk of gastric cancer. Cancer Lett 2002;187:53–60.[CrossRef][Medline]
32. Seedhouse C, Bainton R, Lewis M, Harding A, Russell N, Das-Gupta E. The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia. Blood 2002;100:3761–6.[Abstract/Free Full Text]
33. van Gils CH, Bostick RM, Stern MC, Taylor JA. Differences in base excision repair capacity may modulate the effect of dietary antioxidant intake on prostate cancer risk: an example of polymorphisms in the XRCC1 gene. Cancer Epidemiol Biomarkers Prev 2002;11:1279–84.[Abstract/Free Full Text]
34. Smith TR, Miller MS, Lohman K, et al. Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. Cancer Lett 2003;190:183–90.[CrossRef][Medline]
35. Misra RR, Ratnasinghe D, Tangrea JA, et al. Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. Cancer Lett 2003;191:171–8.[CrossRef][Medline]
36. Zhou W, Liu G, Miller DP, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2003;12:359–65.[Abstract/Free Full Text]
37. Yu MW, Yang SY, Pan IJ, et al. Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2003;95:1485–8.[Abstract/Free Full Text]
38. Cho EY, Hildesheim A, Chen CJ, et al. Nasopharyngeal carcinoma and genetic polymorphisms of DNA repair enzymes XRCC1 and hOGG1. Cancer Epidemiol Biomarkers Prev 2003;12:1100–4.[Abstract/Free Full Text]
39. Varzim G, Monteiro E, Silva RA, Fernandes J, Lopes C. CYP1A1 and XRCC1 gene polymorphisms in SCC of the larynx. Eur J Cancer Prev 2003;12:495–9.[CrossRef][Medline]
40. Moullan N, Cox DG, Angele S, Romestaing P, Gerard JP, Hall J. Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy. Cancer Epidemiol Biomarkers Prev 2003;12:1168–74.[Abstract/Free Full Text]
41. Smith TR, Levine EA, Perrier ND, et al. DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2003;12:1200–4.[Abstract/Free Full Text]
42. Shen M, Hung RJ, Brennan P, et al. Polymorphisms of the DNA repair genes XRCC1, XRCC3, XPD, interaction with environmental exposures, and bladder cancer risk in a case-control study in northern Italy. Cancer Epidemiol Biomarkers Prev 2003;12:1234–40.[Abstract/Free Full Text]
43. Han J, Hankinson SE, De Vivo I, et al. A prospective study of XRCC1 haplotypes and their interaction with plasma carotenoids on breast cancer risk. Cancer Res 2003;63:8536–41.[Abstract/Free Full Text]
44. Shu XO, Cai Q, Gao YT, Wen W, Jin F, Zheng W. A population-based case-control study of the Arg³⁹⁹Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2003;12:1462–7.[Abstract/Free Full Text]
45. Matsuo K, Hamajima N, Suzuki R, et al. Lack of association between DNA base excision repair gene XRCC1 Gln³⁹⁹Arg polymorphism and risk of malignant lymphoma in Japan. Cancer Genet Cytogenet 2004;149:77–80.[CrossRef][Medline]
46. Harms C, Salama SA, Sierra-Torres CH, Cajas-Salazar N, Au W-W. Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer. Environ Mol Mutagen 2004;44:74–82.[CrossRef][Medline]
47. Sanyal S, Festa F, Sakano S, et al. Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis 2004;25:729–34.[Abstract/Free Full Text]
48. Figueiredo JC, Knight JA, Briollais L, Andrulis IL, Ozcelik H. Polymorphisms XRCC1-R399Q and XRCC3-T241M and the risk of breast cancer at the Ontario site of the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 2004;13:583–91.[Abstract/Free Full Text]
49. Forsti A, Angelini S, Festa F, et al. Single nucleotide polymorphisms in breast cancer. Oncol Rep 2004;11:917–22.[Medline]
50. Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM III. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res 2004;32:2193–201.[Abstract/Free Full Text]
51. Wang Y, Spitz MR, Zhu Y, Dong Q, Shete S, Wu X. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair 2003;2:901–8.[CrossRef][Medline]
52. Hao B, Wang H, Zhou K, et al. Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma. Cancer Res 2004;64:4378–84.[Abstract/Free Full Text]
53. Rybicki BA, Conti DV, Moreira A, Cicek M, Casey G, Witte JS. DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2004;13:23–9.[Abstract/Free Full Text]
54. Butkiewicz D, Rusin M, Enewold L, Shields PG, Chorazy M, Harris CC. Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 2001;22:593–7.[Abstract/Free Full Text]
55. Mort R, Mo L, McEwan C, Melton DW. Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer. Br J Cancer 2003;89:333–7.[CrossRef][Medline]
56. Han J, Hankinson SE, Zhang SM, De Vivo I, Hunter DJ. Interaction between genetic variations in DNA repair genes and plasma folate on breast cancer risk. Cancer Epidemiol Biomarkers Prev 2004;13:520–4.[Abstract/Free Full Text]
57. Ratnasinghe DL, Yao SX, Forman M, et al. Gene-environment interactions between the codon 194 polymorphism of XRCC1 and antioxidants influence lung cancer risk. Anticancer Res 2003;23:627–32.[Medline]
58. Stern MC, Umbach DM, Lunn RM, Taylor JA. DNA repair gene XRCC3 codon 241 polymorphism, its interaction with smoking and XRCC1 polymorphisms, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:939–43.[Abstract/Free Full Text]
59. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820–6.[Abstract/Free Full Text]
60. Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis. New York: Oxford University Press; 1994.
61. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992;327:248–54.[Abstract]
62. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.[Abstract/Free Full Text]
63. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003;33:177–82.[CrossRef][Medline]
64. [Editorial] Freely associating. Nat Genet 1999;22:1–2.[CrossRef][Medline]
65. Wacholder S, Rothman N, Caporaso N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev 2002;11:513–20.[Free Full Text]
66. Mitrunen K, Sillanpaa P, Kataja V, et al. Association between XRCC1 Arg³⁹⁹Gln polymorphism and breast cancer risk. AACR 94th Annual Meeting Abstract 567; 2003.
67. Boffetta P, Brennan P, Hung R, et al. Genetic polymorphism of xrcc1, xpd and mgmt on lung cancer risk: a multicentric study in central and eastern Europe. AACR 95th Annual Meeting Abstract 1493; 2004.
68. Freedman ML, Reich D, Penney KL, et al. Assessing the impact of population stratification on genetic association studies. Nat Genet 2004 Apr;36:388–93.

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