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Carcinogenesis Advance Access originally published online on March 29, 2006
Carcinogenesis 2006 27(9):1835-1841; doi:10.1093/carcin/bgl017
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma: a population-based case–control study in Sweden

Weimin Ye1,*, Rajiv Kumar2,3, Gabriela Bacova3, Jesper Lagergren1,4, Kari Hemminki2,3 and Olof Nyrén1

1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet Stockholm, SE 171 77, Sweden
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center 69120 Heidelberg, Germany
3 Department of Bioscience at Novum, Karolinska Institutet Stockholm, SE 141 57, Sweden
4 Unit of Esophageal and Gastric Research, Department of Molecular Medicine and Surgery, Karolinska Institutet Stockholm, SE 171 76, Sweden

*To whom correspondence should be addressed at: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE 171 77, Stockholm, Sweden. Tel: +46 8 52486184; Fax: +46 8 314975; Email: Weimin.Ye{at}ki.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Mechanisms behind the strong associations of esophageal adenocarcinoma risk with gastroesophageal reflux (GOR) and body mass remain to be defined. In a nationwide population-based case–control study, we examined associations of polymorphisms in the DNA repair genes XPD, XPC, XRCC1 and XRCC3 with risk of esophageal adenocarcinoma, squamous-cell carcinoma (SCC) and gastric cardia adenocarcinoma, and paid special attention to possible interactions with symptomatic reflux or body mass. We collected blood samples from 96, 81 and 126 interviewed incident cases of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinoma, respectively, and 472 randomly selected controls, frequency-matched with regard to age and sex. DNA was extracted and polymorphisms in XPD codon 751 (Lys->Gln), codon 312 (Asp->Asn), C insertion in intron 10 of XPD, XPC codon 939 (Lys->Gln), XRCC1 codon 399 (Arg->Gln) and XRCC3 codon 241 (Thr->Met) were examined using PCR–RFLP. Odds ratios (ORs) derived from multivariate logistic regression with adjustments for potential confounding factors estimated relative risks. XPD codon 751 Lys/Gln and Gln/Gln genotypes, compared with Lys/Lys genotype, were both associated with a more than doubled risk for esophageal adenocarcinoma (OR = 2.4; 95% CI = 1.4–4.4; OR = 2.7, 95% CI = 1.3–5.9). The combined effects of these genotypes and symptomatic GOR or body mass showed borderline significant deviation from additivity. Excess risks for esophageal SCC were also noted for XPD 751Gln variant genotypes. Other studied variants were not found to be related to the three tumors. Our study suggests that XPD 751Gln allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.

Abbreviations: BMI, body mass index; CI, confidence interval; GOR, gastroesophageal reflux; ICR, interaction contrast ratio; LD, linkage disequilibrium; OR, odds ratio; MII, multiplicative interaction index; RR, relative risks; SCC, squamous-cell carcinoma; SNPs, single-nucleotide polymorphisms; XPD/XPC, xeroderma pigmentosum complementation group D/C; XRCC1/3, X-ray repair cross-complementing group 1/3 gene


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The incidence of esophageal adenocarcinoma has increased rapidly during the past 30 years in Western countries (1), including Sweden (2). Gastroesophageal reflux (GOR) (3,4), high body mass (5,6), low intake of fruits and vegetables (7) and smoking (8,9) have been identified as risk factors. The mechanisms behind the carcinogenicity of reflux and body mass remain conjectural. Effect modification of the exposure–cancer relationship by functional polymorphisms in known carcinogenic or anticarcinogenic pathways may provide important clues to the mechanisms.

Endogenous or exogenous carcinogens or mutants may cause DNA damages. However, DNA damage is continuously repaired through activation of different pathways that involve polymorphic enzymes. There are at least four pathways of DNA repair, each coping with different types of DNA damage (10). Xeroderma pigmentosum complementation group D and C (XPD, XPC) are 2 out of the >20 genes involved in nucleotide excision repair pathway that repair bulky DNA adducts. Several single-nucleotide polymorphisms (SNPs) have been identified in the XPD gene. Among them, polymorphisms at codon 751 (Lys->Gln) and 312 (Asp->Asn) have been found to be common among Caucasians. Experimental data suggest that these polymorphisms may be functional. In one study, the 751Gln allele was associated with elevated levels of bulky DNA adducts (11), whereas in another study, the 312Asn allele was linked to diminished apoptotic response to UV-induced DNA damage (12). Either 751Gln or 312Asn, or their combination, was reported to be linked with reduced DNA repair capacity (13–15). A novel polymorphism, single base insertion in intron 10 of the XPD gene, has recently been reported and found to be common among Swedish subjects, although its effects remain to be determined (16). A common SNP was also found in codon 939 of the XPC gene (Lys->Gln) (17). The base-excision repair pathway removes small lesions like oxidized or reduced bases, and non-bulky adducts. The X-ray repair cross-complementing group 1 (XRCC1) gene product plays an important role in this pathway. Several evidences indicate that a polymorphism of XRCC1 in codon 399 (Arg->Gln) is functional. The 399Gln allele is associated with higher sister chromatoid exchange frequency induced by smoking or tobacco-specific carcinogens (18,19), higher levels of DNA adducts (19,20) and prolonged cell-cycle delay in response to ionizing radiation (21). Double-strand breaks induced by ionizing radiation or replication errors are handled by a pathway that includes the X-ray repair complementing 3 (XRCC3) gene products. This gene is also polymorphic and the codon 241Met variant has been associated with higher levels of DNA adducts (22).

We postulated that interactions, if any, between enigmatic exposures such as reflux or body mass and functional polymorphisms in genes involved in specific DNA repair pathways would provide clues as to the nature of the mechanisms involved in the carcinogenicity of these exposures. We therefore investigated the possible associations of polymorphisms in XPD, XPC, XRCC1 and XRCC3 with the risks for esophageal adenocarcinoma, esophageal squamous-cell carcinoma (SCC) and gastric cardia adenocarcinoma, and explored possible interactions with environmental and ‘internal’ exposures, such as reflux and body mass, in a Swedish nationwide population-based case–control study.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Design
Parts of the study methods have been described in detail elsewhere (3). Briefly, the study base encompassed ~20 million person-years experienced by the entire native Swedish population <80 years of age during 1995 through 1997. All newly diagnosed patients in the study base with adenocarcinoma of the esophagus or gastric cardia and half of the patients with SCC of the esophagus (born on even-numbered dates) were eligible as cases. Considerable efforts, including establishment of a comprehensive organization with contact persons at all 195 departments of general surgery, thoracic surgery, otorhinolaryngology, oncology and pathology in Sweden, and continuous collaboration with the six regional tumor registries, were made to ensure that every eligible case was identified shortly after diagnosis. All cases were uniformly classified histologically and topographically, and almost all (97%) biopsies and surgical specimens were reviewed by a single pathologist. Endoscopists, surgeons and pathologists gave standardized, detailed descriptions of the location of the tumors. Cancer of the gastric cardia was defined as a tumor with its center within 2 cm proximal, or 3 cm distal, to the gastroesophageal junction. Control subjects were randomly selected from the study base every 6 months using the continuously updated Swedish population register. They were frequency-matched to resemble the age (in 10 years) and sex distribution among the esophageal adenocarcinoma cases. To be eligible, control subjects should be born in Sweden and cancer-free at time of recruitment.

Interview
Patients and control subjects were interviewed face-to-face by specially trained professional interviewers from Statistics Sweden. The questions covered demographic characteristics, living conditions during childhood and adolescence, occurrence of GOR symptoms, anthropometric measures, smoking, alcohol drinking, dietary history, history of medication use and occupational history. To avoid reverse causality, we disregarded GOR symptoms information that had occurred <5 years before the interview. Also, we used tobacco usage information 2 years before interview to determine the user status, and set the reference time point of anthropometric measures and dietary intakes 20 years before interview. The interviewers could not be kept blinded to case–control status but were trained to treat both groups in a strictly equal manner.

Genotyping
Interviewed subjects were asked to donate a venous blood sample. Whole blood samples were stored at –70°C until DNA was extracted. Genomic DNA was isolated using Gentra's Puregene kit (Gentra Systems, Minneapolis, MN).

Genotyping for polymorphisms in XPD Lys751Gln, XPC Lys939Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met were carried out using PCR–RFLP technique. PCR primers for XPD Lys751Gln polymorphism were 5'-CCCCTCTCCCTTTCCTCTGTT-3' (forward) and 5'-GCTGCCTTCTCCTGCGATTA-3' (reverse); for XPC Lys939Gln, 5'-GATGCAGGAGGTGGACTCTCT-3' (forward) and 5'-GTAGTGGGGCAGCAGCAACT-3' (reverse); for XRCC1 Arg399Gln, 5'-GCCCCTCAGATCACACCTAAC-3' (forward) and 5'-CATTGCCCAGCACAGGATAA-3' (reverse); and for XRCC3 Thr241Met, 5'-GCTCGCCTGGTGGTCATC-3' (forward) and 5'-CTTCCGCATCCTGGCTAAAAA-3' (reverse). PCR products were generated by the use of 10 ng genomic DNA in 10 ml reaction volume containing 1x PCR buffer, 2.0 mM MgCl2, 0.11 mM each dNTP, 0.3 mM each primer and 0.3 U Platinum Taq DNA polymerase (Invitrogen, Paisley, UK). PCR products were digested with restriction endonucleases (Fermentas Company, Vilaius, Lithuania or New England Biolabs, Herts, UK) that recognized and cut either wild-type or variant sequences (PstI, PvuII, Msp I, Hsp92 II were used for XPD Lys751Gln, XPC Lys939Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met, respectively). PCR products were digested at 37°C for at least 3 h to overnight. The digested PCR products were resolved on 10% polyacrylamide gel (Bio-Rad, Hercules, CA) and stained with ethidium bromide. XPD Asp312Asn and C insertion in intron 10 were genotyped by a combined SSCP method (16), and the primers used were 5'-GGAGACGGACGCCCACCTG-3' (forward) and 5'-GACGGGGAGGCGGGAAAG-3' (reverse). The genotype results were randomly checked and confirmed by direct DNA sequencing of PCR products. All persons involved in the analyses were blinded to case–control status of the subjects.

Statistical analyses
We checked deviation from Hardy–Weinberg equilibrium among cases and controls by a {chi}2-test, with one degree of freedom. HaploView (http://www.broad.mit.edu/personal/jcbarret/haploview/) was used for measures of pairwise linkage disequilibrium (LD) between SNPs within XPD. Haplotype block structure in XPD was also examined. Individual haplotypes within the same block were estimated by using PHASE 2.0 (http://www.stat.washington.edu/stephens/software.html), a Bayesian method to reconstruct the haplotype using Markov chain Monte Carlo techniques (23). We then modeled the data using unconditional logistic regression to estimate relative risks in the form of odds ratios (ORs) with 95% confidence intervals (CIs). In multivariate modeling, our basic model included the frequency matching variables—age (6 categories) and sex. We considered reflux symptoms (occurring at least once per week), socioeconomic status (reflected by number of years of formal education and categorized into three categories), intake of fruits and vegetables (categorized in three classes), body mass index (BMI) (in quartiles), tobacco smoking status (two years before interview, classified into never smoker, previous smoker and current smoker of any tobacco) and alcohol use (total amount consumed of all types of alcoholic beverages and categorized into four classes) as potential confounding factors.

Gene–environment interaction was estimated by testing departure from risk-ratio multiplicativity or additivity (24). Departure from risk-ratio multiplicativity is equivalent to effect–measure modification or statistical interaction, while departure from additivity measures biological interaction. Owing to limited sample size, we dichotomized the genetic polymorphism by grouping subjects into carriers and non-carriers of the variant allele. Similarly, ‘internal’ and environmental exposures were dichotomized by appropriate grouping. Using the wild-genotype group without environmental exposure as reference, three relative risks (RR) were estimated: RR11 for variant group with environmental exposure, RR10 for variant group without environmental exposure, RR01 for wild-type group with environmental exposure. To test departure from multiplicativity, multiplicative interaction index (MII) was calculated [MII = RR11/(RR10 x RR01)]. MII > 1 implies greater than multiplicative effects; MII = 1 implies multiplicative effects; while MII < 1 implies less than multiplicative effects. P-values for MII were derived from a cross-product term of gene and environment exposure introduced into a multiplicative model. We used interaction contrast ratio (ICR) to test departure from additivity (ICR = RR11 – RR10 – RR01 + 1). ICR > 0 implies greater than additive effects; ICR = 0 implies additive effects; while ICR < 0 implies less than additive effects. CIs of ICR were computed according to the method by Hosmer (25). An ICR can be considered as statistically significant at alpha level 0.05 if its 95% CIs do not include zero. All statistical analyses were performed using SAS 8.2; PROC GENMOD and PROC LOGISTIC were used for logistic regression modeling.

Ethical considerations
The study was approved by all regional ethics committees in Sweden. Individual informed consent was obtained before interview. Informed consent for subsequent genotyping was further sought from all surviving study subjects.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Overall, 189 (88%) of 216 eligible cases of esophageal adenocarcinoma, 167 (73%) of 228 SCC and 262 (84%) of 313 gastric cardia adenocarcinoma were interviewed. Among 1128 randomly selected control subjects, 820 (73%) were also interviewed. The main reasons of non-response among controls in the interview phase were incorrect address information (2%), unwillingness (19%) or physical/mental illnesses (6%). In total, DNA samples were collected from 304 cases and 492 controls who were interviewed. The main reason for non-availability of biological samples from cases was that the clinicians forgot to collect blood samples according to the protocol, while failure to appear at the local health center was the main reason among the control subjects. Only 1 living case and 6 living controls refused to take part in the genotyping, and another 14 living controls could not be traced. They were excluded from the current study. Finally, 96 case patients with esophageal adenocarcinoma, 81 with esophageal SCC, 126 with gastric cardia adenocarcinoma and 472 control subjects were included in the current analysis (Table I). They constituted ~50% of all interviewed case patients, and ~60% of all interviewed controls.


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  		Table I Characteristics of 303 case patients and 472 control subjects who were interviewed and with DNA samples, compared with interviewed subjects but not included in the present analysis

 
The distributions of participants in the present analysis and those who were interviewed but not included in the present analysis by age, place of residence 20 years ago, gender, symptomatic GOR, BMI, smoking, alcohol consumption and intake of fresh vegetables and fruits are listed in Table I. They were similar in most aspects, except that in the subset not included in the present analysis subjects from southern Sweden were overrepresented among cancer cases and current smokers were more common among controls. Multivariably adjusted ORs linked to the interview-derived exposures were similar when using the two datasets; the only exception was more pronounced effects of smoking on risks of the three studied types of cancer in the subset subjected to the present analysis with genotyping data (data not shown).

Among controls, the allele frequency of XPD 751Gln, XPD 312Asn, XPD C-insertion in intron 10, XPC 939Gln, XRCC1 399Gln and XRCC3 241Met was 36.5, 37.3%, 17.7, 37.7, 36.2 and 33.9%, respectively. Except for XRCC1, the genotype distributions did not deviate from Hardy–Weinberg equilibrium. In general, there was little evidence supporting any main effects of XPD 312Asn, XPD C-insertion in intron 10, XPC 939Gln, XRCC1 399Gln and XRCC3 241Met polymorphisms on the risk of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinoma, either combined or stratified into subtypes. However, the XPD 751Gln allele was more common in cancer cases than in controls. Stratified analyses by cancer subtypes revealed that the effects were confined to esophageal cancer. Using wild-type homozygotes as reference, heterogyzotes and homozygotes for XPD 751Gln conferred a >2-fold relative risk for esophageal adenocarcinoma (OR = 2.4, 95% CI = 1.3–4.4; OR = 2.7, 95% CI = 1.3–5.9, respectively). There was also an association with esophageal SCC of almost the same magnitude (OR = 2.0, 95% CI = 1.1–3.9 for heterozygotes; OR = 1.8, 95% CI = 0.7–4.4 for variant homozygotes) (Table II). Further mutual adjustment by including other genetic polymorphisms into models did not change the results materially (data not shown).


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  		Table II DNA repair gene (XRCC1, XPC, XPD and XRCC3) polymorphisms and the risk of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinoma

 
Both XPC and XPD genes belong to the nucleotide excision repair pathway. We further checked the combined effects of polymorphisms in these genes. Cancer cases tended to have more variant alleles than controls, especially for esophageal adenocarcinoma. When using those without or with only one variant allele as reference, subjects with three or more had a 2-fold excess risk for esophageal adenocarcinoma (Table III). We also checked pairwise LD between the three polymorphisms within the XPD gene, and found a strong LD (D' = 1.0) between XPD (Asp312Asn) and C insertion in intron 10 of the XPD gene, and a moderate LD (D' = 0.6) between XPD (Asp312Asn) and XPD (Lys751Gln). XPD (Asp312Asn) and C insertion in intron 10 of the XPD gene were found to be in the same haplotype block, and we thus used these two SNPs to infer individual haplotypes (AG/GA/GG). None of the estimated haplotypes were significantly associated with the risk of any of the three cancer types under study (data not shown).


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  		Table III Number of variant alleles in XPD (Lys751Gln), XPD(Asp312Asn), C insertion in intron 10 of the XPD gene and XPC (Lys939Gln) and the risk of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinoma

 
Notwithstanding the relatively small sample size, we also explored combined effects of the XPD 751Gln polymorphism and some environmental exposures (Table IV). For the three tumors studied, there was little evidence that combined effects of XPD 751Gln polymorphism and symptomatic GOR, BMI, low intake of fresh vegetables and fruits and smoking, respectively, deviated from multiplicativity. However, for esophageal adenocarcinoma, combined effects between XPD 751Gln polymorphism and symptomatic GOR (ICR = 9.7, 95% CI = –1.0, 20.4, P-value = 0.08) or BMI (ICR = 3.9, 95% CI –1.2, 8.9, P-value = 0.14) seemed to depart from additivity.


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  		Table IV Combined effectsa of XPD codon 751 polymorphism and symptomatic GOR, body mass index, intake of fresh vegetables and fruits, and smoking on the risk of esophageal adenocarcinoma, esophageal SCC and gastric cardia adenocarcinomab

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is, to the best of our knowledge, the first population-based study that has explored the association between DNA repair gene polymorphisms and risk of esophageal adenocarcinoma. Our study results indicate that carriage of the XPD 751Gln allele may predispose an individual to esophageal adenocarcinoma. Homozygote variants had a slightly higher risk than heterozygotes. Although the ICR was statistically non-significant, the combined effects of this genetic polymorphism and each of the ‘internal’ exposures—GOR and obesity—tended to be greater than the simple sums; rather, the effects seemed to multiply. Excess risks for esophageal SCC were also noted for XPD 751 Gln variant genotypes. Polymorphisms in XPD codon 312, XPD C-insertion in intron 10, XPC codon 939, XRCC1 codon 399 and XRCC3 codon 241 did not seem to modulate risk for any of the histological types of esophageal cancer or gastric cardia adenocarcinoma.

Strengths of our study include the population-based design, the almost complete case ascertainment, the efforts made to minimize misclassification of tumors among the cases and the high participation rate in the interview phase. Detailed interview data enabled us to control for a range of conceivable confounding factors. The relatively low proportion of cases and controls who donated whole blood may, however, raise concerns about the internal validity of the study. Our results could have been biased if characteristics of the subjects with DNA samples differed from those of subjects without DNA samples, but comprehensive demographic and exposure data obtained at interview with non-participating cases and controls suggest that selection bias is unlikely to have importantly influenced our results. We found obvious deviation from Hardy–Weinberg equilibrium for XRCC1 399, which was also found in another study among Caucasians (26). Concerns about systematic errors in genotyping and population stratification may be raised. However, our careful quality control and lack of deviation from Hardy–Weinberg equilibrium for the other five polymorphisms studied indicated that such systematic genotyping error is unlikely. Careful check-up of geographical distribution among those with or without blood samples revealed only small difference. Thus, population stratification also appears very unlikely to be the explanation. In future, formal test of population difference may be performed by using randomly selected genetic markers (27).

Previous molecular epidemiological studies have found that the XPD 751Gln allele is associated with increased risks for head and neck cancer (28), melanoma skin cancer (29) and lung cancer (30,31). However, inconsistent findings were also reported, including absence of any association with lung (32–34), and paradoxical inverse associations with esophageal adenocarcinoma (35) and basal cell carcinoma (36). Previous reports on the association between XPD 312Asn allele and cancer risk are also controversial, including either positive (31,37) or null results (14,38). Reasons for the previous inconsistent findings may include small sample sizes, inappropriate study design and maybe different LD with other SNPs in different populations. There is no previous epidemiological study on the association between XPD C-insertion in intron 10 and cancer risk.

Our results indicated a null association between the XPC 939Gln, XRCC1 399Gln, XRCC3 241Met alleles and the risk for any of the three cancer types studied. The XPC 939Gln allele has recently been reported to be associated with an excess risk for bladder cancer (39), lung cancer (40) and melanoma (41). However, a negative association has also been noted for lung cancer (42). As opposed to our findings, the XRCC1 399Gln allele was shown to be associated with esophageal cancer (mostly SCC) risk in one previous study (43), while other studies failed to confirm this association (44,45). Of interest is that in one recent study, XRCC1 399Gln allele was inversely associated with the risk of GOR diseases and Barrett's esophagus, but not esophageal adenocarcinoma (35). XRCC3 241Met was reportedly associated with an increased risk for melanoma skin cancer (38), while no association could be demonstrated with esophageal adenocarcinoma (35) and bladder cancer (46).

The obviously conflicting results from previous molecular epidemiological studies of the association between DNA repair gene polymorphisms and cancer risk warrant cautious interpretation of our results. The study sample size is relatively small; thus chance findings cannot be excluded. Further, we did not have enough power to detect a modest excess risk. Future studies should be based on larger samples, and they should explore in greater detail the combined effects of genes involved in the specific pathway. Further limitations of our study included multiple statistical testing, which increases the risk for Type-I errors, and the potential selection bias as smoking was underrepresented in control subjects who donated blood samples. Although other mechanisms of cancer protection, like apoptosis, may take over and conceal the effects of deficient repair, strong interaction between the effects of an ‘internal’ or external exposure and effects of defects in a specific DNA repair pathway could potentially provide important clues to the nature of the DNA damage caused by the exposure. For instance, if the suggested interaction of GOR with the XPD 751Gln polymorphism—but not with functional polymorphisms in other DNA repair pathways—will be confirmed in a larger study, it is likely that the carcinogenecity of reflux at some stage involves the formation of bulky adducts. In conclusion, the XPD 751Gln allele may be a risk factor for both major histological types of esophageal cancer particularly for esophageal adenocarcinoma. Further studies are warranted to confirm this finding.


   Acknowledgments
 
This study was funded by a grant (R01 CA57947-03) from the National Cancer Institute, and two grants (4559-B01-01XAA, 4758-B02-01XAB) from the Swedish Cancer Society.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Blot W.J. and McLaughlin J.K. (1999) The changing epidemiology of esophageal cancer. Semin. Oncol. 26:2–8.[Web of Science][Medline]
  2. Hansson L.E., Sparen P., Nyren O. (1993) Increasing incidence of both major histological types of esophageal carcinomas among men in Sweden. Int. J. Cancer 54:402–407.[Web of Science][Medline]
  3. Lagergren J., Bergstrom R., Lindgren A., Nyren O. (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma [see comments]. N. Engl. J. Med. 340:825–831.[Abstract/Free Full Text]
  4. Chow W.H., Finkle W.D., McLaughlin J.K., Frankl H., Ziel H.K., Fraumeni J.F. Jr. (1995) The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia. JAMA 274:474–477.[Abstract/Free Full Text]
  5. Lagergren J., Bergstrom R., Nyren O. (1999) Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann. Intern. Med. 130:883–890.[Abstract/Free Full Text]
  6. Chow W.H., Blot W.J., Vaughan T.L., et al. (1998) Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J. Natl Cancer Inst. 90:150–155.[Abstract/Free Full Text]
  7. Terry P., Lagergren J., Hansen H., Wolk A., Nyren O. (2001) Fruit and vegetable consumption in the prevention of oesophageal and cardia cancers. Eur. J. Cancer Prev. 10:365–369.[CrossRef][Web of Science][Medline]
  8. Lagergren J., Bergstrom R., Lindgren A., Nyren O. (2000) The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int. J. Cancer 85:340–346.[CrossRef][Web of Science][Medline]
  9. Gammon M.D., Schoenberg J.B., Ahsan H., et al. (1997) Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia [see comments]. J. Natl Cancer Inst. 89:1277–1284.[Abstract/Free Full Text]
  10. Goode E.L., Ulrich C.M., Potter J.D. (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol. Biomarkers Prev. 11:1513–1530.[Abstract/Free Full Text]
  11. Palli D., Russo A., Masala G., Saieva C., Guarrera S., Carturan S., Munnia A., Matullo G., Peluso M. (2001) DNA adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample. Int. J. Cancer 94:121–127.[CrossRef][Web of Science][Medline]
  12. Seker H., Butkiewicz D., Bowman E.D., Rusin M., Hedayati M., Grossman L., Harris C.C. (2001) Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. Cancer Res. 61:7430–7434.[Abstract/Free Full Text]
  13. Lunn R.M., Helzlsouer K.J., Parshad R., Umbach D.M., Harris E.L., Sanford K.K., Bell D.A. (2000) XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21:551–555.[Abstract/Free Full Text]
  14. Spitz M.R., Wu X., Wang Y., Wang L.E., Shete S., Amos C.I., Guo Z., Lei L., Mohrenweiser H., Wei Q. (2001) Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res. 61:1354–1357.[Abstract/Free Full Text]
  15. Hemminki K., Xu G., Angelini S., Snellman E., Jansen C.T., Lambert B., Hou S.M. (2001) XPD exon 10 and 23 polymorphisms and DNA repair in human skin in situ. Carcinogenesis 22:1185–1188.[Abstract/Free Full Text]
  16. Kumar R., Angelini S., Hemminki K. (2003) Simultaneous detection of the exon 10 polymorphism and a novel intronic single base insertion polymorphism in the XPD gene using single strand conformation polymorphism. Mutagenesis 18:207–209.[Abstract/Free Full Text]
  17. Khan S.G., Metter E.J., Tarone R.E., Bohr V.A., Grossman L., Hedayati M., Bale S.J., Emmert S., Kraemer K.H. (2000) A new xeroderma pigmentosum group C poly(AT) insertion/deletion polymorphism. Carcinogenesis 21:1821–1825.[Abstract/Free Full Text]
  18. Abdel-Rahman S.Z., Soliman A.S., Bondy M.L., Omar S., El-Badawy S.A., Khaled H.M., Seifeldin I.A., Levin B. (2000) 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. 159:79–86.[CrossRef][Web of Science][Medline]
  19. Duell E.J., Wiencke J.K., Cheng T.J., Varkonyi A., Zuo Z.F., Ashok T.D., Mark E.J., Wain J.C., Christiani D.C., Kelsey K.T. (2000) Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 21:965–971.[Abstract/Free Full Text]
  20. Lunn R.M., Langlois R.G., Hsieh L.L., Thompson C.L., Bell D.A. (1999) XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res. 59:2557–2561.[Abstract/Free Full Text]
  21. Hu J.J., Smith T.R., Miller M.S., Mohrenweiser H.W., Golden A., Case L.D. (2001) Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis 22:917–922.[Abstract/Free Full Text]
  22. Matullo G., Guarrera S., Carturan S., Peluso M., Malaveille C., Davico L., Piazza A., Vineis P. (2001) DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case–control study. Int. J. Cancer 92:562–567.[CrossRef][Web of Science][Medline]
  23. Stephens M., Smith N.J., Donnelly P. (2001) A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68:978–989.[CrossRef][Web of Science][Medline]
  24. Greenland S. and Rothman K.J. (1998) Concepts of interaction. In Rothman K.J. and Greenland S. (Eds.). Modern Epidemiology (Lippincott-Raven Publishers, Philadelphia) pp. 329–342.
  25. Hosmer D.W. and Lemeshow S. (1992) Confidence interval estimation of interaction. Epidemiology 3:452–456.[Web of Science][Medline]
  26. Duell E.J., Holly E.A., Bracci P.M., Wiencke J.K., Kelsey K.T. (2002) A population-based study of the Arg399Gln polymorphism in X-ray repair cross-complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma. Cancer Res. 62:4630–4636.[Abstract/Free Full Text]
  27. Cardon L.R. and Palmer L.J. (2003) Population stratification and spurious allelic association. Lancet 361:598–604.[CrossRef][Web of Science][Medline]
  28. Sturgis E.M., Zheng R., Li L., Castillo E.J., Eicher S.A., Chen M., Strom S.S., Spitz M.R., Wei Q. (2000) XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case– control analysis. Carcinogenesis 21:2219–2223.[Abstract/Free Full Text]
  29. Tomescu D., Kavanagh G., Ha T., Campbell H., Melton D.W. (2001) Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. Carcinogenesis 22:403–408.[Abstract/Free Full Text]
  30. Xing D., Tan W., Wei Q., Lin D. (2002) Polymorphisms of the DNA repair gene XPD and risk of lung cancer in a Chinese population. Lung Cancer 38:123–129.[CrossRef][Web of Science][Medline]
  31. Hou S.M., Falt S., Angelini S., Yang K., Nyberg F., Lambert B., Hemminki K. (2002) The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis 23:599–603.[Abstract/Free Full Text]
  32. David-Beabes G.L., Lunn R.M., London S.J. (2001) No association between the XPD (Lys751G1n) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 10:911–912.[Free Full Text]
  33. Park J.Y., Lee S.Y., Jeon H.S., et al. (2002) Lys751Gln polymorphism in the DNA repair gene XPD and risk of primary lung cancer. Lung Cancer 36:15–16.[CrossRef][Web of Science][Medline]
  34. Misra R.R., Ratnasinghe D., Tangrea J.A., Virtamo J., Andersen M.R., Barrett M., Taylor P.R., Albanes D. (2003) 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. 191:171–178.[CrossRef][Web of Science][Medline]
  35. Casson A.G., Zheng Z., Evans S.C., Veugelers P.J., Porter G.A., Guernsey D.L. (2005) Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Carcinogenesis 26:1536–1541.[Abstract/Free Full Text]
  36. Dybdahl M., Vogel U., Frentz G., Wallin H., Nexo B.A. (1999) Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 8:77–81.[Abstract/Free Full Text]
  37. Liang G., Xing D., Miao X., Tan W., Yu C., Lu W., Lin D. (2003) Sequence variations in the DNA repair gene XPD and risk of lung cancer in a Chinese population. Int. J. Cancer 105:669–73.[CrossRef][Web of Science][Medline]
  38. Winsey S.L., Haldar N.A., Marsh H.P., Bunce M., Marshall S.E., Harris A.L., Wojnarowska F., Welsh K.I. (2000) A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res. 60:5612–5616.[Abstract/Free Full Text]
  39. Sanyal S., Festa F., Sakano S., Zhang Z., Steineck G., Norming U., Wijkstrom H., Larsson P., Kumar R., Hemminki K. (2004) Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis 25:729–734.[Abstract/Free Full Text]
  40. Vogel U., Overvad K., Wallin H., Tjonneland A., Nexo B.A., Raaschou-Nielsen O. (2005) Combinations of polymorphisms in XPD, XPC and XPA in relation to risk of lung cancer. Cancer Lett. 222:67–74.[CrossRef][Web of Science][Medline]
  41. Blankenburg S., Konig I.R., Moessner R., et al. (2005) Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case–control study. Carcinogenesis 26:1085–1090.[Abstract/Free Full Text]
  42. Lee G.Y., Jang J.S., Lee S.Y., et al. (2005) XPC polymorphisms and lung cancer risk. Int. J. Cancer 115:807–813.[CrossRef][Web of Science][Medline]
  43. Lee J.M., Lee Y.C., Yang S.Y., Yang P.W., Luh S.P., Lee C.J., Chen C.J., Wu M.T. (2001) Genetic polymorphisms of XRCC1 and risk of the esophageal cancer. Int. J. Cancer 95:240–246.[CrossRef][Web of Science][Medline]
  44. Xing D., Qi J., Miao X., Lu W., Tan W., Lin D. (2002) 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 100:600–605.[CrossRef][Web of Science][Medline]
  45. Hao B., Wang H., Zhou K., et al. (2004) Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma. Cancer Res. 64:4378–4384.[Abstract/Free Full Text]
  46. Stern M.C., Umbach D.M., Lunn R.M., Taylor J.A. (2002) DNA repair gene XRCC3 codon 241 polymorphism, its interaction with smoking and XRCC1 polymorphisms, and bladder cancer risk. Cancer Epidemiol. Biomarkers Prev. 11:939–943.[Abstract/Free Full Text]
Received October 14, 2005; revised March 8, 2006; accepted March 15, 2006.


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