ERCC2, ERCC1 polymorphisms and haplotypes,cooking oil fume and lung adenocarcinoma risk in Chinese non-smoking females

Background

Excision repair cross-complementing group 1 (ERCC1) and group 2 (ERCC2) proteins play important roles in the repair of DNA damage and adducts. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ERCC2 751, 312 and ERCC1 118 polymorphisms and the risk of lung adenocarcinoma in Chinese non-smoking females.

Methods

A hospital-based case-control study of 285 patients and 285 matched controls was conducted. Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, each person donated 10 ml blood for biomarker testing. Three polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

This study showed that the individuals with the combined ERCC2 751AC/CC genotypes were at an increased risk for lung adenocarcinoma compared with those carrying the AA genotype [adjusted odds ratios (OR) 1.64, 95% confidence interval (CI) 1.06-2.52]. The stratified analysis suggested that increased risk associated with ERCC2 751 variant genotypes (AC/CC) was more pronounced in individuals without exposure to cooking oil fume (OR 1.98, 95%CI 1.18-3.32) and those without exposure to fuel smoke (OR 2.47, 95%CI 1.46-4.18). Haplotype analysis showed that the A-G-T and C-G-C haplotypes were associated with increased risk of lung adenocarcinoma among non-smoking females (ORs were 1.43 and 2.28, 95%CIs were 1.07-1.91 and 1.34-3.89, respectively).

Conclusion

ERCC2 751 polymorphism may be a genetic risk modifier for lung adenocarcinoma in non-smoking females in China.     

XRCC3基因多态性与西北地区妇女乳腺癌的关联性研究

目的：通过对中国西北地区妇女乳腺癌与健康人群XRCC3基因多态性位点的研究,找出基因多态性与乳腺癌发病的相关性。方法：采集西北地区的517例乳腺癌患者和1 008例健康人群外周血,提取DNA后采用高通量芯片检测方法,测定XRCC3基因rs861534、rs861537、rs3212092和rs861530共4个多态性位点的基因分型。结果：Logistic回归分析发现XRCC3 rs861534位点的AG/AA基因型,病例组与对照组比较差异有统计学意义（P < 0.01,OR=0.36;P=0.013,OR=0.08）,同时,GG+AG基因型与对照组比较差异有统计学意义（P < 0.01）,XRCC3 rs861530位点的Logistic回归分析显示AG+AA基因型与对照组比较差异有统计学意义（P=0.044）。相关临床病理学指标分析显示rs861537位点的GG/AG基因型在ER⁺与ER^-患者中的分布差异有统计学意义（P=0.048,OR=1.50）。rs3212092位点的CC+CT基因型在Her-2^-与Her-2⁺患者中的分布差异具有统计学意义（P=0.027,OR=2.06）。结论：在中国西北地区妇女人群中XRCC3基因rs861534和rs861530两个位点的多态性与乳腺癌的发病有相关性。在XRCC3 rs861537位点,GG/AG基因型ER⁺携带者可能具有较高的乳腺癌内分泌治疗风险;在rs3212092位点,携带CT和TT基因型的Her-2⁺表达患者具有明显的乳腺癌转移复发风险。     

XRCC1基因多态性与肺癌易感性关系的研究进展

X射线损伤修复的交叉互补基因 (X rayrepaircrosscomplementinggroup 1,XRCC1)是一种DNA损伤修复基因 ,其多态性能够改变DNA修复功能和效率 ,影响肿瘤易感性。分析了XRCC1基因结构、功能及其多态性与肺癌易感性的关系     

XRCC3 polymorphisms and risk of lung cancer

In a nested case-cohort study, we have investigated the occurrence of lung cancer in relation to polymorphisms in the double strand DNA repair gene XRCC3. Among 54,220 members of a Danish prospective cohort study aged 50-65 at entry, 265 lung cancer cases were identified and a sub-cohort, matched by age, sex and duration of smoking, comprising of 272 individuals was used for comparison. Ninety percent of both cases and comparison group were ever-smokers. Three previously studied polymorphisms; XRCC3 A4541G (5'UTR), A17893G (IVS5-14) and C18067T (T241M) were combined into haplotypes. The four most frequent haplotypes accounted for 98% of the genotypes. Homozygosity for the haplotype AAC was associated with a 4.91 times higher risk of lung cancer (confidence interval, 95% CI = 1.06-22.81) compared with the GAC haplotype. The polymorphism XRCC3 IVS6 C1571T was found to co-segregate with the AAC haplotype, and homozygous carriers of the variant T-allele had a 4.47 (CI = 1.34-14.96) times higher risk of lung cancer compared with homozygous carriers of the wild type allele. Our results indicate that XRCC3 IVS6 C1571T and the associated haplotype AAC are associated with relatively high risk of lung cancer.     

XRCC1 polymorphisms and severe toxicity in lung cancer patients treated with cisplatin-based chemotherapy in Chinese population

Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. The predictability of DNA repair XRCC1 (X-ray repair cross-complementing group 1 protein) single nucleotide polymorphisms (SNPs) for cisplatin-based grades 3 and 4 chemotherapy-related toxicity in patients with newly diagnosed advanced lung cancer was evaluated. The genotypes of XRCC1 at the Arg194Trp, and Arg399Gln sites were determined by PCR-based restriction fragment length polymorphism (RFLP) methods. There was no statistically significant association between either the Arg194Trp or the Arg399Gln polymorphisms and hematologic grade 3 or 4 toxicity. However, carrying at least one variant XRCC1 Arg399Gln allele (399Arg/Gln or 399Gln/Gln) was associated with a significantly increased risk of overall grade 3 or 4 toxicity (odds ratio, 2.05; 95% confidence interval, 1.02-4.10; p=0.04); and grade 3 or 4 gastrointestinal toxicity (odds ratio, 2.53; 95% confidence interval, 1.06-6.03; p=0.03). Our results suggested that patients carrying at least one variant XRCC1 Arg399Gln allele have a 2.5-fold increased risk of grade 3 or 4 gastrointestinal toxicity when treated with first-line cisplatin-based chemotherapy.     

DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population

X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair (BER) and nucleotide excision repair (NER) of DNA repair pathways, respectively. Polymorphisms of DNA repair gene XRCC1 and XPD has recently been identified, and there is a growing body of evidence that these polymorphisms may have some phenotypic significance. To investigate the role of XRCC1 polymorphisms (codon 194 and codon 399) and XPD polymorphism (codon 751) in lung cancer, a population-based case-control study of 109 lung cancer patients and 109 healthy control subjects (individually matched on age and gender) in a Chinese population was conducted. XRCC1 and XPD genotypes were identified using PCR-restriction fragments length polymorphism technique. Conditional logistic regression analysis revealed that XRCC1 codon 194Trp/Trp genotype was associated with a borderline increased risk of lung cancer [adjusted odd ratio (OR) = 3.06; confidence interval (CI) 0.94-9.92]. The XPD 751 Lys allele (combined Lys/Lys and Lys/Gln genotypes) was associated with a significantly increased risk of lung cancer (OR = 3.19; CI 1.01-10.07). The risk of lung cancer increased more than additive interaction (adjusted OR = 8.77; CI 1.47-52.31) for the individuals with both putative high-risk genotypes of XRCC1 194 Trp/Trp and XPD 751 Lys allele. Our results suggested that the genotypes of XRCC1 194Trp/Trp and XPD 751 Lys allele might be the risk genotypes for lung cancer in Chinese population.     

Fumes from meat cooking and lung cancer risk in Chinese women.

Chinese women are recognized to have a high incidence of lung cancer despite a low smoking prevalence. Several studies have implicated domestic exposure to cooking fumes as a possible risk factor, although the exact carcinogens have yet to be identified. Heterocyclic amines are known carcinogens, which have been identified in cooked meat, and also in fumes generated during frying or grilling of meats. We conducted a case-control study of 303 Chinese women with pathologically confirmed, primary carcinomas of the lung and 765 controls to examine the association between exposure to meat cooking and lung cancer risk. Data on demographic background, smoking status, and domestic cooking exposure, including stir-frying of meat, were obtained by in-person interview while in hospital. The response rates among eligible cases and controls were 95.0 and 96.9%, respectively. The proportion of smokers (current or ex-smokers) among cases and controls was 41.7 and 13.1%, respectively. Adenocarcinomas comprised 31.5% of cancers among smokers and 71.6% among nonsmokers. When cases were compared with controls, the odds ratio (OR) for lung cancer (all subtypes) among ex-smokers was 4.3 [95% confidence interval (CI) 2.7-6.8] and that among current smokers was 5.0 (95% CI, 3.4-7.3). Among smokers, women who reported that they stir-fried daily in the past had a significantly increased risk of lung cancer (adjusted OR, 2.0; 95% CI, 1.0-3.8) and among these women, risk was enhanced for those who stir-fried meat daily (OR, 2.7; 95% CI, 1.3-5.5). Women who stir-fried daily but cooked meat less often than daily did not show an elevated risk (OR, 1.0. 95% CI, 0.5-2.4). Risk was further increased among women stir-frying meat daily who reported that their kitchen was filled with oily fumes during cooking (OR, 3.7; 95% CI, 1.8-7.5). These cooking practices on their own did not increase risk among nonsmokers in our study population. Our results suggest that inhalation of carcinogens, such as heterocyclic amines generated during frying of meat, may increase the risk of lung cancer among smokers. Further studies in different settings are warranted to examine this possibility, which may also help to explain the higher risk observed among women smokers compared with men.     

XRCC1多态性与乳腺癌易感性

XRCC1是一个低度外显的基因，其编码的蛋白质在碱基切除修复过程中是不可缺少的。该基因多态性会导致所编码蛋白发生改变，从而影响DNA修复，可能引起肿瘤的易感性。XRCC1基因多态性与乳腺癌易感性的关系仍然存在争论，其相关性需进一步深入研究。     

CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women

We examined CYP1A1 (I462V) and GSTM1 null polymorphisms in 200 female cases and 144 female controls selected from a population-based case-control study of lung cancer conducted in northeast China, where the rates of lung cancer among Chinese women are especially high. The CYP1A1 codon 462 point mutation in exon 7 (I462V) causes an Ile-Val substitution near the heme binding site. This mutation correlates with inducibility of aryl hydrocarbon hydrolase (AHH) activity, which activates polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke and in indoor air pollution from coal-burning stoves, a risk factor for lung cancer in this study population. We found that the CYP1A1 I462V genotype (combined ile/val and val/val) was significantly associated with lung cancer risk. The odds ratio (OR) was 2.5 (95% confidence interval [CI], 1.55-4.03) after adjustment for significant risk factors such as age, ever smoking status, family history of cancer, and eye irritation when cooking. The association was more pronounced among non-smokers (OR=3.67; 95% CI, 1.85-7.28) than among smokers (OR=1.74, 95% CI, 0.85-3.54). In contrast, we did not find a significant association with the GSTM1 null genotype. In summary, our case-control study of lung cancer among women in northeast China revealed an elevated risk associated with the CYP1A1 I462V genotype, but no interaction with smoking or indoor air pollution was found.     

XRCC1 polymorphisms and head and neck cancer

Inter-individual differences in DNA repair capacity have been demonstrated using a variety of phenotypic assays, including reduced repair among patients with squamous cell carcinoma of the head and neck (SCCHN). The XRCC1 DNA repair gene may facilitate DNA strand break and base excision repair. A recent case-control study of SCCHN reported associations with two polymorphisms of the XRCC1 including the exon 6, 194Arg/Arg genotype and the exon 10, 399 Gln/Gln genotype. We conducted an analysis of these two XRCC1 polymorphisms using data from a case-control study of SCCHN. Among white subjects, we found a weak elevation in risk associated with the Arg194Trp polymorphism [odds ratio (OR)=1.3; 95% confidence interval (CI)=0.6-2.9] and a decreased risk for the Arg399Gln polymorphism (OR=0.6; CI=0.4-1.1). We found a markedly decreased odds ratio for the Gln/Gln genotype among whites (OR=0.1; CI=0.04-0.6) and blacks (OR=0.01; CI=0.0004-0.3). We also found a suggestion of an interaction between the Arg194Trp and Arg399Gln polymorphisms and tobacco use. Additional epidemiologic and functional studies are needed to resolve the importance of these XRCC1 polymorphisms in SCCHN.     

Genetic polymorphisms of DNA repair genes XRCC1 and XRCC3 and risk of colorectal cancer in Chinese population

Aim: The distribution of DNA repair gene XRCC1 and XRCC3 genotypes was used to assess the potential influence of genetic polymorphisms on risk of colorectal cancer, and interactions with other factors. Methods: a 1:2 matched case-control study was conducted with 485 cases and 970 controls. XRCC1 and XRCC2 genotype polymorphisms were based upon duplex polymerase-chain-reaction with the confronting-two-pairprimer (PCR-CTPP) method. Results:The XRCC1 399Cln allele polymorphism was found to be associated with an increased colorectal cancer risk, while an non-significant inversely association was noted for XRCC3 241Thr/Thr genotype. We also found that individuals with the XRCC1 399 Gln and XRCC3 241Met alleles had an elevated risk, while XRCC3241Thr/Thr was proctective. Conclusion: This study is the first to provide evidence of importance of XRCC1 and XRCC3 gene polymorphisms for risk of colorectal cancer in the Chinese population.     

DNA修复基因XRCC1多态性与肺癌易感性的关系

目的:研究碱基切除修复基因XRCC1多态性与肺癌易感性的关系。方法:采用病例-对照研究,收集太原市原发性肺癌患者111例为病例组,同时随机抽取210名健康居民作为对照组,并进行流行病学调查。应用PCR-RFLP方法分析由内切酶MspI识别XRCC1基因Arg399Gln位点的多态性,比较不同基因型与肺癌易感性的关系,以及基因多态性与吸烟之间对肺癌易感性的交互作用。结果:XRCC1密码子399杂合基因型Arg/Gln可能对鳞癌有较弱的保护效应,并可能降低吸烟者患肺癌的危险性。而纯合突变基因型Gln/Gln与和吸烟的存在协同作用可显著提高肺癌的危险度。结论:碱基切除修复基因XRCC1密码子399的多态性可能会对肺癌易感性产生影响,并可能与吸烟量之间存在一定的协同作用。     

Dietary isothiocyanates, glutathione S-transferase -M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore.

Chinese populations consume a diet relatively high in isothiocyanates (ITCs), a derivative of cruciferous vegetables known to have cancer-protective effects. This class of compounds is metabolized by the glutathione S-transferase family of enzymes, which are also involved in the detoxification of tobacco-related carcinogens such as polycyclic aromatic hydrocarbons and alkyl halides. We evaluated the association between dietary isothiocyanate intake, GSTM1 and GSTT1 polymorphisms, and lung cancer risk in 420 Chinese women: 233 histologically confirmed lung cancer patients and 187 hospital controls. Among these, 58.8% of cases and 90.3% of controls were lifetime nonsmokers. An allele-specific PCR method was used to detect the presence or absence of the GSTM1 and GSTT1 genes in DNA isolated from peripheral blood. Higher weekly intake of ITCs (above the control median value of 53.0 micromol) reduced the risk of lung cancer to a greater extent in smokers [adjusted odds ratio (OR), 0.31; 95% confidence interval (CI), 0.10-0.98] than nonsmokers (OR, 0.70; 95% CI, 0.45-1.11). The inverse association was stronger among subjects with homozygous deletion of GSTM1 and/or GSTT1. Among nonsmokers with GSTM1-null genotype, higher intake of ITCs significantly reduced the risk of lung cancer (OR, 0.54; 95% CI, 0.30-0.95), an effect not seen among those with detectable GSTM1 (OR, 1.07; 95% CI, 0.50-2.29). Our results, in a Chinese female population, are consistent with the hypothesis that ITC is inversely related to the risk of lung cancer, and we show that among nonsmokers this effect may be primarily confined to GST-null individuals. Conjugation and elimination of ITCs is enhanced in GST-non-null relative to -null individuals, such that the GST metabolic genotype modifies the protective effect of ITCs on lung cancer development.     

Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women

The high incidence of lung cancer among Chinese females, despite a low smoking prevalence, remains poorly explained. Cooking fume exposure during frying could be an important risk factor. We carried out a population-based case-control study in Hong Kong. Cases were Chinese female nonsmokers with newly diagnosed primary lung cancer. Controls were female nonsmokers randomly sampled from the community, frequency matched by age groups. Face-to-face interviews were conducted using a standardized questionnaire. The "total cooking dish-years," categorized by increments of 50, was used as a surrogate of cooking fumes exposure. Multiple unconditional logistic regression was used to estimate the odds ratios (OR) for different levels of exposure after adjusting for various potential confounding factors. We interviewed 200 cases and 285 controls. The ORs of lung cancer across increasing levels of cooking dish-years were 1, 1.17, 1.92, 2.26, and 6.15. After adjusting for age and other potential confounding factors, the increasing trend of ORs with increasing exposure categories became clearer, being 1, 1.31, 4.12, 4.68, and 34. The OR of lung cancer was highest for deep-frying (2.56 per 10 dish-years) followed by that of frying (1.47), and stir-frying had the lowest OR (1.12) among the three methods. Cumulative exposure to cooking by means of any form of frying could increase the risk of lung cancer in Hong Kong nonsmoking women. Practical means to reduce exposures to cooking fumes should be given top priority in future research.     

XRCC1 polymorphisms and pancreatic cancer: A meta-analysis

Objective:To assess the association between X-ray repair cross-complementating group 1 (XRCC1) polymorphisms and pancreatic cancer.Methods:We searched MEDLINE,Web of Science and HuGE Navigator at June 2010,and then quantitatively summarized associations of the XRCC1 polymorphisms with pancreatic cancer risk using meta-analysis.Results:Four studies with 1343 cases and 2302 controls were included.Our analysis found:at codon 194,the Trp allele did not decrease pancreatic cancer risk (Arg/Arg versus Trp/Trp:OR=0.97;95% CI:0.48-1.96;P=0.97;Arg/Arg versus Arg/Trp:OR=0.89;95% CI:0.70-1.13;P=0.55;Arg/Trp versus Trp/Trp:OR=1.06;95% CI:0.52-2.16;P=0.90);at codon 280,only a study showed a nonsignificant association between single nucleotide polymorphism with pancreatic cancer risk;at codon 399,the Gln allele also showed no signi?cant effect on pancreatic cancer compared to Arg allele (Arg/Arg versus Gln/Gln:OR=0.94;95% CI:0.74-1.18;Arg/Arg versus Arg/Gln:OR=0.97;95% CI:0.83-1.13;Arg/Gln versus Gln/Gln:OR=0.97;95% CI:0.77-1.22).The shape of the funnel plot and the Egger’s test did not detect any publication bias.Conclusion:There is no evidence that XRCC1 polymorphisms (Arg194Trp,Arg280His,and Arg399Gln) are associated with pancreatic cancer risk.     

Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus

Population-based studies have reported significant associations between specific genetic polymorphisms and breast cancer susceptibility. A number of studies have demonstrated that common variants of genes involved in the DNA repair pathway act as low penetrance breast cancer susceptibility alleles. We aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the DNA repair genes XRCC1, XRCC2 and XRCC3 and breast cancer in MASTOS, a population-based case–control study of 1,109 Cypriot women with breast cancer diagnosed between 40 and 70 years and 1,177 age-matched healthy controls. Five coding SNPs were genotyped including rs1799782, rs25489 and rs25487 in XRCC1, rs3218536 in XRCC2 and rs861539 in XRCC3. Homozygous XRCC1 280His carriers had an increased risk of breast cancer (odds ratio 4.68; 95% CI 1.01–21.7; P = 0.03). The XRCC2 188His allele was associated with a marginal protective effect for breast cancer (odds ratio 0.79; 95% CI 0.62–1.00; P = 0.05). No significant associations were observed between the other three SNPs and breast cancer. This study suggests that genetic variation in SNPs in XRCC1 and XRCC2 genes may influence breast cancer susceptibility.     

Association of XRCC1 gene single nucleotide polymorphisms and susceptibility to pancreatic cancer in Chinese

The human X-ray repair cross-complementing group 1 gene (XRCC1) is an important candidate gene for affecting pancreatic cancer (PC) risk. The objective of this study was to detect whether the c.1471G?>?A and c.1686C?>?G polymorphisms of XRCC1 gene influence PC risk. The association of XRCC1 genetic variants with PC risk was analyzed in 328 PC patients and 350 controls by the polymerase chain reaction-restriction fragment length polymorphism and created restriction site-polymerase chain reaction method. Our data suggested that the genotypes and alleles from these two genetic variants were statistically associated with PC risk. For c.1471G?>?A, the AA genotype was associated with the decreased risk of developing PC compared to GG wild genotype (odds ratio (OR)?=?0.43, 95 % confidence intervals (CI) 0.26–0.70, chi-squared (χ ²)?=?11.91, P?=?0.001). For c.1686C?>?G, the risk of PC was significantly lower for GG genotype in comparing to CC wild genotype (OR?=?0.48, 95 % CI 0.29–0.81, χ ²?=?7.98, P?=?0.005). The A allele of c.1471G?>?A and G allele of c.1686C?>?G genetic variants could contribute to decrease the risk of PC (for c.1471G?>?A: A vs G, OR?=?0.65, 95 % CI 0.52–0.82, χ ²?=?13.71, P?<?0.001, for c.1686C?>?G: G vs C, OR?=?0.70, 95 % CI 0.55–0.88, χ ²?=?9.42, P?=?0.002). Our findings indicate that the c.1471G?>?A and c.1686C?>?G polymorphisms of XRCC1 gene are associated with PC risk in Chinese population.     

DNA repair gene XRCC1 polymorphisms, smoking, and esophageal cancer risk

To investigate the effect of X-ray repair cross complementing 1 (XRCC1) genetic polymorphisms on esophageal cancer risk, we determined XRCC1 polymorphisms at codon 194 (Arg --> Trp) and codon 399 (Arg --> Gln) in 135 patients with esophageal squamous cell carcinoma (ESCC) and 152 normal controls from hospitals. Although polymorphism at codon 194 was not associated with risk for ESCC, we found that the frequency of XRCC1 399 Gln/Gln genotype in ESCC patients (14.1%) was significantly higher than that in normal controls (3.3%), and that XRCC1 399 Gln/Gln genotype was associated with an increased risk of ESCC (odds ratio (OR) = 5.15, 95% confidence interval (CI): 2.42-0.93). In addition, we found that the risk for smoker increased 4.2-fold than non-smokers in the 399 Gln/Gln genotype (OR = 4.20, 95% CI: 2.37-7.44). These results suggest that XRCC1 399 Gln/Gln genotype may contribute to the risk of ESCC and modify risk associated with smoking.     

Mouse models of XRCC1 DNA repair polymorphisms and cancer

DNA damage plays a major role in mutagenesis, carcinogenesis and aging. A gene that is emerging as an essential element in the repair of both damaged bases and single-strand breaks (SSB) is XRCC1. XRCC1 has been shown to have a large number of single-nucleotide polymorphisms (SNPs), several of which are being increasingly studied in cancer epidemiology investigations, in part because of their relative high frequency in the population. Although association trends with specific cancer types have occasionally been shown in a variety of ethnic backgrounds, there are often conflicting reports that weaken any substantial conclusions. The functional significance of these SNPs is still largely unknown. XRCC1 is an excellent prototype to provide a forum for determining how epidemiological cancer association studies with DNA repair gene polymorphisms can be validated or refuted. The focus is on the utilization of in silico data and biochemical studies in cell lines and existing mouse models to help provide a framework for the development of new mutant mouse lines that mimic human polymorphisms. These mouse lines will provide the next generation of mammalian tools for carcinogen exposure studies relevant to human cancer and variations in XRCC1, and provide the basis for investigating groups of genes and polymorphisms in an animal model.     

Genetic polymorphisms of XRCC1 and risk of gastric cancer

Coding polymorphisms of the DNA repair gene XRCC1 have been shown to affect the DNA repair capacity and to be associated with genetic susceptibility to carcinogenesis. In our association study between three amino acid substitution polymorphisms of XRCC1 (Arg194Trp, Arg280His, and Arg399Gln) and the risk of gastric cancer in the Korean population, none of the polymorphisms were associated with increased risk of gastric cancer. We then extended our study by building haplotypes of the entire XRCC1 gene with six single neuclotide polymorphisms (SNPs), including two novel polymorphisms at the 5'-flanking sequence. When haplotype frequencies in cases and controls and haplotype-specific odds ratios (ORs) were estimated, haplotype A (194Trp, 280Arg, and 399Arg) was associated with significant reduction in gastric cancer risk (adjusted OR=0.65, 95% CI=0.43-0.99) whereas haplotype D (194Arg, 280Arg, and 399Arg alleles) was a risk type for gastric cancer (adjusted OR=1.57, 95% CI=0.93-2.65). The association with the haplotype D was more pronounced in the cancers of antrum (adjusted OR=2.06, 95% CI=1.03-2.00). Our results suggest that the haplotype estimation is advantageous for association studies of such a complex disease as gastric cancer.