Geneenvironment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk
Hidemi Ito1,2,8,
Keitaro Matsuo1,
Nobuyuki Hamajima3,
Tetsuya Mitsudomi4,
Takahiko Sugiura5,
Toshiko Saito1,
Tetsuo Yasue6,
Kyoung-Mu Lee7,
Daehee Kang7,
Keun-Young Yoo7,
Shigeki Sato2,
Ryuzo Ueda2 and
Kazuo Tajima1
1 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya Aichi, 2 Department of Internal Medicine and Molecular Science, Nagoya City University, Graduate School of Medical Sciences, Nagoya Aichi, 3 Department of Preventive Medicine, Biostatistics and Medical Decision Making, Nagoya Graduated School of Medicine, Nagoya Aichi, 4 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya Aichi, 5 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya Aichi, 6 Division of Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya Aichi, Japan and 7 Department of Preventive Medicine, General Surgery and Cancer Research Institute, Seoul National University, Seoul, South Korea
8 To whom correspondence should be addressed Email: hidemi{at}aichi-cc.jp
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Abstract
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APE1 (apurinic/apyrimidinic endonuclease 1) and XRCC1 (X-ray cross-complementing group 1) are DNA repair proteins that play important roles in the base excision repair (BER) pathway. Polymorphisms in their encoding genes are associated with altered DNA repair capacity and thus may impact on cancer risk. In the present case-control study with 178 Japanese incident lung cancer cases and 449 age- and sex-matched controls, we investigated the geneenvironment interaction among APE1 Asp148Glu, XRCC1 Arg399Gln and smoking habit in lung cancer risk. The results were analyzed by using conditional logistic regression models, adjusted for age, sex and smoking status. The adjusted odds ratio for the current smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotype as compared with the never smokers with the Asp/Asp genotype were 3.01 (95% CI 1.396.51, P = 0.005), 2.73 (95% CI 1.295.77, P = 0.008) and 7.33 (95% CI 2.9318.3, P < 0.001), respectively. The geneenvironment interaction between current smoking and APE1 148Glu/Glu genotype was statistically significant (OR 3.59, 95% CI 1.2810.1, P = 0.015). When APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were evaluated together, the adjusted odds ratios for the current smokers with 01, 2 and 34 of APE1 148Glu or XRCC1 399Gln alleles as compared with never smokers with the 0 of these alleles were 2.96 (95% CI 1.575.58, P = 0.001), 3.86 (95% CI 1.858.05, P < 0.001) and 6.01 (95% CI 2.2516.1, P < 0.001), respectively. The geneenvironment interaction between current smoking and three or more APE1 148Glu or XRCC1 399Gln alleles was statistically significant (OR 2.44, 95% CI 1.009.22, P = 0.049). The OR for the geneenvironment interaction of Glu/Glu genotype of APE1 codon 148 with heavy smoking was 1.04 (95% CI 0.382.90, P = 0.936) and that with light smoking was 2.67 (95% CI 1.007.68, P = 0.049). These results suggest that APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms might modify the risk of lung cancer attributable to cigarette smoking exposure.
Abbreviations: AP, apurinic/apyrimidinic; APE1, apurinic/apyrimidinic endonuclease 1; BER, base excision repair; XRCC1, X-ray cross-complementing group 1
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Introduction
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Cigarette smoke contains large quantities of carcinogens, including polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, which damage DNA by covalent binding or oxidation, following activation in vivo into benzo[a]pyrene-diol epoxide (1). Although extensive prospective epidemiologic data have clearly established cigarette smoking as the major cause of lung cancer (2), only a fraction of cigarette smokers develop smoking-related lung cancer (3). This variation has been suggested to be due, in part, to genetically determined variation in carcinogen metabolism (4) and/or in the capacity of DNA repair (513), which is essential in protecting the genome of cells.
The apurinic/apyrimidinic (AP) endonuclease (APE1) and DNA repair enzyme X-ray repair cross-complementing group 1 (XRCC1) coordinate (14) and play a central role in the DNA base excision repair (BER) pathway, which operates on small lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents (15). APE1, the rate-limiting enzyme in the BER pathway (16), assembles pol ß onto AP sites and allows pol ß and ligase III to engage in DNA repair (17). Although the APE1 Asp148Glu polymorphism does not result in reduced endonuclease activity (18), the Glu allele may have higher sensitivity to ionizing radiation (19). Only one result has so far been reported about its relevance to lung cancer risk and this showed no significant association (20). XRCC1 interacts with ligase III, DNA polymerase ß and poly (ADP-ribose) polymerase (PARP) in the C-terminal, N-terminal and central regions of XRCC1, respectively. Contradictory results have been reported about the association of the XRCC1 Arg399Gln polymorphism with either DNA repair capacity (21,22) or the risk of lung cancer (20,2328). The Gln allele of this polymorphism is associated with increased levels of DNA damage that may be due to reduced DNA repair, as reflected in a higher level of DNA adducts (21,29), glycophorin A variants (21,30) and bleomycin sensitivity (31) as well as chromatid exchange frequencies (22). However, other authors found no association between this polymorphism and DNA adducts (30,32). A joint effect of APE1 Asp148Glu and XRCC1 Arg399Gln allele genotypes has been reported regarding elevation of sensitivity to ionizing radiation (19).
Cigarette smoking may induce DNA damage (33) and individuals with a reduced capacity of DNA repair would be expected to have more carcinogenDNA adducts in their tissue (13). Indeed, lung cancer patients may have a lower capacity of DNA repair when compared with healthy subjects and this may modulate the risk of lung cancer associated with smoking (11,12,34). Polymorphisms of DNA repair genes that impair their function should theoretically predispose an individual to development of tobacco-related cancers such as those in the lung (34). Therefore, we conducted the present hospital-based case-control study to test this biological hypothesis by evaluating the relationship between polymorphisms of two DNA repair genes, APE1 and XRCC1, smoking and the risk of lung cancer.
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Materials and methods
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Study subjects
Cases and controls were first-visit outpatients at Aichi Cancer Center Hospital (ACCH) who were enrolled in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) (35,36). All subjects gave written informed consent to participate in the study, completed a self-administered questionnaire and provided peripheral blood. Cases of lung cancer newly diagnosed on the basis of pathologic examination at ACCH from November 2000 to April 2002 were deemed eligible, a total of 178 cases. Controls were selected by random sampling from 2158 cancer-free individuals without a past history of cancer, who visited ACCH and provided peripheral blood between November 2000 and October 2001. They were confirmed not to have cancer by the hospital-based cancer registry system by the end of 2002 and were frequency-matched to cases by sex and age group. Consequently, 178 cases and 449 controls were selected for the study.
The Institutional Ethical Review Board of Aichi Cancer Center approved this study before it was commenced (approved number 41-2).
Genotyping procedure
DNA was extracted from the buffy coat fraction using QIAamp blood mini kit (Qiagen, Valencia, CA) and genotyping for APE1 Glu148Asp and XRCC1 Arg399Gln polymorphisms was performed by a PCRCTPP (PCR with confronting two-pair primers) method (37). For the APE1 Glu148Asp (2197 T to G) polymorphism, extracted DNA was amplified with the four primers by Ampli Taq Gold (Perkin-Elmer, Foster City, CA); F1, 5'-CCT ACG GCA TAG GTG AGA CC-3'; R1, 5'-TCC TGA TCA TGC TCC TCC-3'; F2, 5'-TCT GTT TCA TTT CTA TAG GCG AT-3'; and R2, 5'-GTC AAT TTC TTC ATG TGC CA-3'. PCR conditions were 1-min denaturation at 95°C followed by 30 cycles of 95°C for 1 min, 60°C for 1 min, and 72°C for 1 min, with a 5-min extension at 72°C. Primer pairs F1 and R1 for the G allele (148Glu), F2 and R2 for the T allele (148Asp) produced allele-specific bands of 167- and 236-bp, respectively, as well as a 360-bp common band. For XRCC1 Arg399Gln (28152 G to A), extracted DNA was amplified with the four primers by Ampli Taq Gold (Perkin-Elmer, Foster City, CA); F1, 5'-TCC CTG CGC CGC TGC AGT TTC T-3'; R1, 5'-TGG CGT GTG AGG CCT TAC CTC C-3'; F2, 5'-TCG GCG GCT GCC CTC CCA-3'; and R2, 5'-AGC CCT CTG TGA CCT CCC AGG C-3'. PCR conditions were 1-min denaturation at 94°C followed by 30 cycles of 94°C for 1 min, 59°C for 1 min, and 72°C for 1 min, with a 10-min extension at 72°C. Primer pairs F1 and R1 for the G allele (399Arg) and F2 and R2 for the A allele (399Gln) produced allele-specific bands of 447- and 222-bp, respectively, as well as a 630-bp common band. Both of APE1 and XRCC1 genotyping were confirmed by PCRRFLP with BafI (19) and MspI digestion (33), respectively.
Statistical analysis
All statistical analyses were performed with STATA Version 8 software (STATA, College Station, TX). The observed genotype frequencies for controls were compared with those calculated from HardyWeinberg disequilibrium theory. The odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression analysis with adjustment for age, sex and smoking status. Smoking status at interview was classified into three categories: current smokers (individuals who either were currently smoking or had quit smoking within the previous 1 year); never smokers [those who smoked <100 cigarettes in their lifetime (before diagnosis for cases)]; former smokers (those who had quit smoking 1 year and more previously). For analysis of combined effect of APE1 and XRCC1 genotypes, three categories, 01, 2 and 34 were defined according to the number of rare allele (APE 148Glu and XRCC1 399Gln) in APE1 and XRCC1 genotypes. Geneenvironment interactions were estimated by the logistic regression model (38), which included an interaction term as well as a variables for exposure (smoking), genotypes (APE1 or XRCC1) or haplotype (number of rare alleles) and potential confounders (age and sex).
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Results
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As shown in Table I, the analysis included 178 cases and 449 controls. Because of frequency-matching by sex and age strata, there were no significant differences in the sex distribution and the mean age between the cases (male, 70.2%, mean ± SD, 62.9 ± 9.1, range 3679 years) and the controls (male, 69.9% mean ± SD, 62.6 ± 9.1, range 3579 years) (P = 0.943 for sex distribution, two-sided
2-test and P = 0.677 for mean age, t-test). Histological subtypes of the cases were: adenocarcinoma, 62.4% (n = 111); squamous cell carcinoma, 19.7% (n = 35); small cell carcinoma, 12.4% (n = 22) and others, 5.5% (n = 10). There were more current smokers in the cases (50.6%) than in the controls (29.2%) (P < 0.001). In addition, there were more heavy smokers (41 or more of pack-years of smoking) in the cases (69.6%) than in the smoker controls (33.7%) among smokers (P < 0.001).
Figure 1 shows representative results of genotyping of APE1 Asp148Glu and XRCC1 Arg399Gln genotypes by the PCRCTPP methods. The genotyping results were completely in accordance with those generated by the PCRRFLP method. The APE1 148Glu allele frequencies for controls and cases were 0.39 and 0.41 and the genotype distribution among controls was in accordance with the HardyWeinberg equilibrium law (P = 0.250,
2 test): Asp/Asp, 35.4%; Asp/Glu, 50.3%; Glu/Glu, 14.3%. The distribution among cases was: Asp/Asp, 34.8%; Asp/Glu, 47.2%; Glu/Glu, 18.0%. The XRCC1 399Gln allele frequencies for controls and cases were 0.25 and 0.26 and the genotype distribution among controls was again in accordance with the HardyWeinberg equilibrium law: Arg/Arg, 56.5%; Arg/Gln, 37.7%; Gln/Gln, 5.8% (P = 0.750,
2 test). The distribution among cases was: Arg/Arg, 55.0%; Arg/Gln, 37.1%; Gln/Gln, 7.9%. Thirty-two cases (18%) and 64 controls (14.3%) were homozygous for the codon 148 polymorphism (148 Glu/Glu) of APE1 (P = 0.507,
2 test), and 14 cases (7.9%) and 26 controls (5.8%) were homozygous for codon 399 polymorphism (399 Gln/Gln) of XRCC1 (P = 0.635,
2 test) (Table II).

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Fig. 1. Representative results for the APE1 Asp148Glu (lanes 13) and XRCC1 Arg399Gln (lanes 46) polymorphisms by the PCRCTPP method. DNA fragments stained with ethidium bromide are shown. Lane M, markers; lane 1, Asp/Asp; lane 2, Asp/Glu; lane 3, Glu/Glu; lane 4, Arg/Arg; lane 5, Arg/Gln; lane 6, Gln/Gln.
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Table II. APE1 codon 148 genotype and XRCC1 codon 399 genotype frequencies and odds ratios in lung cancer patients and controls
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The crude ORs for APE1 Asp/Glu and Glu/Glu as compared with Asp/Asp genotype were not statistically significant and risks were virtually unchanged after adjustment for age, sex, smoking status and pack-years of smoking (adjusted OR = 0.99, 95% CI 0.661.49 for Asp/Glu and 1.29 0.752.21 for Glu/Glu, respectively; Table II). Likewise, the ORs for XRCC1 Arg/Gln and Gln/Gln compared with Arg/Arg genotype were not statistically significant (adjusted OR = 1.02 for Arg/Gln, 0.691.50 and 1.36, 0.652.79 for Gln/Gln, respectively; Table II). When we examined the combined APE1 and XRCC1 genotypes, similar results were obtained [adjusted OR = 1.18, 0.791.75 for the subjects with 2 rare alleles (APE1 148Glu and XRCC1 399Gln) and 1.22, 0.632.37 for the subjects with 34 rare alleles, respectively; Table II].
The adjusted ORs for joint effect of environmental factor (smoking habit) and APE1 codon 148 and XRCC1 codon 399 genotype are shown in Table III. For APE1 codon 148 genotype, the impact of the Glu/Glu genotype in current smokers appeared higher than that of Asp/Asp and Asp/Glu genotypes. ORs of current smokers with Asp/Asp, Asp/Glu and Glu/Glu genotypes were 3.01 (95% CI 1.396.51, P = 0.005), 2.73 (95% CI 1.295.77, P = 0.008) and 7.33 (95% CI 2.9318.3, P < 0.001), respectively, when compared with never smokers with Asp/Asp genotypes. The OR for the geneenvironment interaction between Glu/Glu genotype of APE1 codon 148 and current smoking in lung cancer risk was 3.59 (95% CI 1.2810.12, P = 0.015). For XRCC1 codon 399 genotype, on the other hand, OR for current smokers with Gln/Gln genotype (3.15, 95% CI 1.045.79, P < 0.042) was similar to that with Arg/Arg and Arg/Gln (OR = 3.39, 95% CI 1.766.50, P < 0.001 and OR = 3.67, 95% CI 1.807.46, P < 0.001, respectively), and this geneenvironment interaction between Gln/Gln genotype and current smoking in lung cancer risk was not statistically significant (OR, 0.95, 95% CI, 0.461.96, P = 0.893). Joint effects of combined APE1 and XRCC1 genotypes and the smoking habit are also shown in Table III. The impact of 34 rare alleles among current smokers appeared substantially higher than that of 2 and fewer rare alleles. Adjusted ORs were 2.96 (95% CI 1.575.58, P = 0.001) for current smokers with 01 rare alleles, 3.86 (95% CI 1.858.05, P < 0.001) for those with 2 rare alleles and 6.01 (95% CI 2.2516.1, P < 0.001) among those with 34 rare alleles. The geneenvironment interaction between 3 and 4 rare alleles and current smoking was statistically significant (adjusted OR 2.44, 95% CI 1.029.22, P = 0.049).
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Table III. Adjusted odds ratios and 95% CI for the joint effect of smoking habit and polymorphisms of APE1 Aps148Glu and XRCC1 Arg399Gln, and combined these genotypes
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The adjusted ORs for joint effect of tobacco exposure (pack-years of smoking) and APE1 codon 148 and XRCC1 codon 399 genotype are shown in Table IV. The impact of the APE1 148Glu/Glu genotype in light smokers appeared substantially higher than that in heavy smokers. The ORs of heavy smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotypes were 5.56 (95% CI 2.3513.2, P < 0.001), 7.24 (95% CI 3.1616.6, P < 0.001) and 8.38 (95% CI 3.0922.7, P < 0.001), respectively, when compared with never smokers with Asp/Asp genotypes. And the OR for the geneenvironment interaction between Glu/Glu genotype of APE1 codon 148 and heavy smoking in lung cancer risk was 1.04 (95% CI 0.382.90, P = 0.936). On the other hand, the ORs for light smokers with Asp/Asp, Asp/Glu and Glu/Glu genotypes were 1.24 (95% CI 0.522.94, P = 0.623), 0.68 (95% CI 0.291.63, P = 0.389) and 2.62 (95% CI 3.0922.7, P = 0.049), respectively, when compared with never smokers with Asp/Asp genotypes, and the OR for the geneenvironment interaction between Glu/Glu genotype of APE1 codon 148 and light smoking in lung cancer risk was 2.67 (95% CI 1.007.68, P = 0.049). For XRCC1 Arg399Gln polymorphism, comparison of joint effects with light smoking could not be estimated due to small sample size in this category and the differences of the ORs among heavy smokers between the polymorphisms was not observed (8.07, 95% CI 3.8217.0, P < 0.001 for Arg/Arg, 5.41, 95% CI 2.4611.9, P < 0.001 for Arg/Gln and 7.55, 95% CI 2.2824.9, P = 0.001 for Gln/Gln, respectively). For combined APE1 and XRCC1 genotypes and the smoking exposure, the impact of 34 rare alleles among light smokers also appeared higher than among heavy smokers. Geneenvironment interactions with the 34 rare alleles regarding lung cancer risk were 2.20 (95% CI 0.4510.8, P = 0.329) for light smoking and 1.43 (95% CI 0.375.48, P = 0.602) for heavy smoking.
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Table IV. Adjusted odds ratios and 95% CI for the joint effect of smoking habit and polymorphisms of APE1 Aps148Glu and XRCC1 Arg399Gln, and combined these genotypes
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Discussion
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Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Based on this hypothesis, we examined the relationships between polymorphisms of two DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, smoking and the risk of lung cancer. We found a statistically significant interaction of current/light smoking with APE1 Asp148Glu polymorphism but not with XRCC1 Arg399Gln. Moreover, we found the combination of these polymorphisms to have a statistically significant joint effect with current smoking. In contrast, we did not find significant associations with APE1 Asp148Glu polymorphism alone as well as XRCC1 Arg399Gln polymorphism regarding the risk of lung cancer. To the best of our knowledge, this is the first report showing a geneenvironment interaction between the APE1 and XRCC1 genotypes and cigarette smoking with regard to lung cancer risk.
In this study, the allele frequency of APE1 codon 148 Glu (0.39) was consistent with the previous studies (18,19). However, Misra et al. (20) reported Glu allele frequency of 0.52 for APE1 codon 148 among male smokers. That of XRCC1 399Gln (0.26) was much lower, as well as in Koreans (0.22) (39), in Chinese (0.250.27) (23,39) and in Taiwanese (0.26) (21) than those in Caucasians (0.340.38) (21,25,29). The differences in allele frequencies detected among these studies might be due to ethnic variation, heterogeneity of study populations and different sample sizes.
The polymorphism of APE1 Asp148Glu has so far only been looked at regarding lung cancer risk among male smokers and a lack of any link has been reported for Caucasians (20). Regarding biological significance, the Glu allele of this polymorphism appears to be associated with hypersensitivity to ionizing radiation (19). Another study found a possible effect on endonuclease and DNA binding ability for APE1 codon 148 Glu allele (18). Although the authors did not observe APE1 148 Glu protein defective in endonuclease and DNA binding activity, their results suggested a reduced ability to communicate with other BER proteins giving rise to reduced BER efficacy. The available evidence is thus basically accordant with our observations.
The XRCC1 Arg399Gln polymorphism occurs within the BRCA C-terminal domain, which interacts with PARP (40). Considering the important roles of BRCA1 and PARP in DNA repair, the XRCC1 399Gln may have functional significance. This polymorphism has been reported to be linked with a higher level of DNA adducts (21,29), glycophorin A variants (21,30), bleomycin sensitivity (31) and chromatid exchange frequencies (22). Based on potential biological significance, this polymorphism has been evaluated epidemiologically in many cancers. However, no association was found with esophageal cancer (32,41), bladder cancer (32) or malignant lymphoma (42). On the other hand, possible associations have been reported for pancreatic cancer (43), prostate cancer (44), breast cancer (45) and gastric cancer (46). Regarding lung cancer, two studies in Caucasians (22,24), an American-African study (26) and a Korean study (27) demonstrated significant association with the XRCC1 Arg399Gln polymorphism. A Caucasian study (26), Chinese studies (23,39) and our study failed to demonstrate significant association, although the trend was positive, in line with the significant associations (22,24). Although the reason for inconsistency across various types of cancer is unclear, one may say that the effect of this polymorphism on lung cancer is consistent across studies and is accordant with biological mechanisms. For different polymorphism of XRCC1, Arg194Trp, inconsistent results have been reported regarding lung cancer risk and geneenvironment interaction with smoking, alcohol and serum antioxidants (23,39,47).
Although the result for joint effect of polymorphisms of APE1 Asp148Glu and XRCC1 Arg399Gln on lung cancer risk was not significant, it suggested that the individuals with 34 rare alleles are at increased risk of lung cancer. This result is in agreement with the evidence that APE1 and XRCC1 coordinate to the BER pathway (14) and that the joint effect of two genotypes yields higher sensitivity to ionizing radiation (19).
The risk for lung cancer among smokers is thought to increase with cumulative tobacco exposure (48), and genetic susceptibility to lung cancer may depend on the level of exposure to tobacco smoke (49,50). Therefore, we examined further geneenvironment interaction between tobacco smoke exposure (pack-years of smoking) and the polymorphisms of APE1 and XRCC1. When the subjects were divided into two groups according to cumulative cigarette consumption (
40 pack-years and >40 pack-years of smoking), we found that light smoking had a statistically significant interaction with the Glu/Glu genotype of APE1 codon 148 regarding risk of lung cancer, while heavy smoking did not. Although comparison of joint effects of the light and heavy smoking with XRCC1 Arg399Gln polymorphism could not be estimated due to small sample size in this study, such epidemiological comparisons have been recently conducted (2628). In these studies, results among Caucasians, African-Americans and Koreans have consistently demonstrated that the XRCC1 Gln allele may confer higher risk in light smokers. One study with healthy Italian subjects had significantly higher DNA adduct levels in lymphocytes with Gln/Gln genotypes only in never smokers, but not ever smokers (32). The exact mechanism of how cigarette smoking changes the DNA repair capacity by each genotype of these DNA repair polymorphisms is unknown. One possible mechanism is that, at high levels of exposure, the DNA repair capacity is saturated even in individuals having higher repair capacity (49,50).
Although we have evaluated the feasibility of using non-cancer outpatients participating in HERPACC program as controls and found them to reflect the general population in Japan (51), the present investigation, as a hospital-based case-control study, has several limitations. Our results may be biased by the relatively small number of subjects in the various subgroups and therefore need to be duplicated by others. Further studies with a larger sample and more complete measures of tobacco exposure are needed to clarify the geneenvironment (smoking) interaction. Furthermore, we only evaluated the specific distribution of APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms but not the other polymorphisms of these two genes, including the APE1 Gln51His, Ile64Val and Gly241Arg and the XRCC1 Arg194Trp, because of relatively low allele frequencies for these polymorphisms and limited information regarding their functional significance (18,21,22,25,26). Cigarette smoke is a complex mixture of substances, and APE1 and XRCC1 contribute partially to BER. It is possible that polymorphisms of other genes not evaluated in this study could play a role in lung cancer risk, but evaluation of more polymorphisms would require larger sample sizes. Although the exact biological mechanisms for the geneenvironment (smoking) interaction related to the APE1 and XRCC1 phenotypes as consequences of these polymorphisms could not be clarified, this study did provide important additional evidence of geneenvironment interactions between APE1 and XRCC1 polymorphisms and smoking.
In conclusion, APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms appear to play an important role in modifying the direction and magnitude of the association between cigarette smoking exposure and lung cancer risk.
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Acknowledgments
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The authors are grateful to Ms Naomi Takeuchi, Ms Keiko Asai and Ms Hiroko Fujikura for their technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas of Cancer from the Japanese Ministry of Education, Science, Culture, Sports, Science and Technology.
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Received November 1, 2003;
revised March 10, 2004;
accepted March 18, 2004.