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1.
A population-based study of the Arg399Gln polymorphism in X-ray repair cross- complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma 总被引:11,自引:0,他引:11
XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA strand breaks and base damage from a variety of endogenous and exogenous oxidants including tobacco smoke. One genetic polymorphism (G-->A, Arg-->Gln at codon 399) occurs within a poly(ADP-ribose) polymerase binding region and within the central breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1. The variant 399Gln allele of XRCC1 has been associated with elevated biomarkers of DNA damage in human cells. We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic DNA, and questionnaire information from 309 cases of pancreatic adenocarcinoma and 964 controls that were part of a population-based, case-control study conducted in the San Francisco Bay Area between 1994 and 2001. We genotyped individuals using a mass spectrometry-based method. Because smoking and obesity are known and suspected pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m(2)). We also assessed potential gene-gene interactions between polymorphisms in XRCC1 and CYP1A1, GSTT1, and GSTM1. We found little or no evidence for an association between XRCC1 genotype and pancreatic cancer among Caucasians, African-Americans, or Asians. There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men. Relative to never active or passive smokers with the Arg/Arg genotype, the age- and race-adjusted ORs and ICRs (95% confidence limits) for heavy smoking (>or=41 pack-years) were: for Gln/Gln or Arg/Gln genotypes [women OR = 7.0 (2.4, 21), ICR = 3.1 (0.03, 6.2); men OR = 2.4 (1.1, 5.0), ICR = 1.3 (-0.20, 2.8)]; and for the Arg/Arg genotype [women OR = 2.2 (0.73, 6.4); men OR = 1.5 (0.68, 3.2)]. Analyses of combined genotypes suggested an interaction between XRCC1 (Gln/Gln or Arg/Gln) and GSTT1/GSTM1-null/null among women but not among men. There was no evidence of interaction between XRCC1 genotype and body mass index. Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced pancreatic cancer. Our findings, including stronger associations and interactions among women, require replication in additional study populations. 相似文献
2.
Thyagarajan B Anderson KE Folsom AR Jacobs DR Lynch CF Bargaje A Khaliq W Gross MD 《Cancer Detection and Prevention》2006,30(4):313-321
BACKGROUND: Genetic variation in DNA repair may contribute to differences in the susceptibility of several cancers. We evaluated two polymorphisms in the base excision repair pathway (BER) (XRCC1; Arg194Trp and Arg399Gln) and one polymorphism in the double strand DNA repair pathway (XRCC3; Thr241Met) for their association with breast cancer risk. METHODS: The association was analyzed in a nested case control study of 460 breast cancer cases and 324 cancer-free controls within the Iowa Women's Health Cohort. DNA was obtained from blood samples or paraffin embedded tissues (PET) and all samples were genotyped by one of three genotyping platforms-PCR-RFLP, PCR-INVADER, or Sequenom. RESULTS: None of the three polymorphisms studied were significantly associated with breast cancer risk (XRCC1: Arg194Trp (OR=1.21, 95% CI: 0.78-1.88); Arg399Gln (OR=1.20, 95% CI: 0.80-1.79); XRCC3: Thr241Met (OR=1.04, 95% CI: 0.76-1.41). CONCLUSIONS: These results suggest that independently these polymorphisms of XRCC1 and XRCC3 genes do not contribute significantly to the genetic susceptibility of breast cancer. 相似文献
3.
DNA修复基因XRCC1多态性与肺癌易感性的关系 总被引:3,自引:0,他引:3
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。 相似文献
4.
Zhibin Hu Hongxia Ma Feng Chen Qingyi Wei Hongbing Shen 《Cancer epidemiology, biomarkers & prevention》2005,14(7):1810-1818
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. 相似文献
5.
Polymorphisms in the DNA repair gene XRCC1 and breast cancer. 总被引:17,自引:0,他引:17
E J Duell R C Millikan G S Pittman S Winkel R M Lunn C K Tse A Eaton H W Mohrenweiser B Newman D A Bell 《Cancer epidemiology, biomarkers & prevention》2001,10(3):217-222
X-ray repair cross complementing group 1 (XRCC1) encodes a protein involved in base excision repair. We examined the association of polymorphisms in XRCC1 (codon 194 Arg-->Trp and codon 399 Arg-->Gln) and breast cancer in the Carolina Breast Cancer Study, a population-based case-control study in North Carolina. No association was observed between XRCC1 codon 194 genotype and breast cancer, and odds ratios (ORs) were not modified by smoking or radiation exposure. A positive association for XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes compared with Arg/Arg was found among African Americans (253 cases, 266 controls; OR = 1.7, 95% confidence interval, 1.1-2.4) but not whites (386 cases, 381 controls; OR =1.0, 95% confidence interval, 0.8-1.4). Among African-American women, ORs for the duration of smoking were elevated among women with XRCC1 codon 399 Arg/Arg genotype (trend test; P < 0.001) but not Arg/Gln or Gln/Gln (P = 0.23). There was no difference in OR for smoking according to XRCC1 codon 399 genotype in white women. ORs for occupational exposure to ionizing radiation were stronger for African-American and white women with codon 399 Arg/Arg genotype. High-dose radiation to the chest was more strongly associated with breast cancer among white women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures. However, interpretation of our results is limited by incomplete knowledge regarding the biological function of XRCC1 alleles. 相似文献
6.
《Asian Pacific journal of cancer prevention》2013,14(9):5275-5279
Background: The XRCC1 (X-ray repair cross complimenting group-I) gene in BER (base excision repair)pathway is essential for DNA repair process. Polymorphisms in this gene are associated with variations in the repairefficiency which might predispose individuals to development of various cancers. Two variants of XRCC1gene(at codon 399), Gln/Gln and Arg/Gln, have been shown to be related to lowered DNA repair capacity andincreased genomic instability in multiple studies. Hence our investigation focused on genotyping these variantsto correlate with other multiple risk factors in lung cancer (NSCLC) patients since we hypothesized that thesevariants of the XRCC1 gene might influence disease susceptibility. Materials and Methods: We examined thefrequency of the polymorphism in one hundred cases and an almost equal number of controls after recordingtheir demographics with a structured questionnaire. Genomic DNA from blood samples was extracted for PCRstudies, followed by RFLP to determine the variants. The significance of the data was statistically analyzed.Results: The three genotypes in cases and controls were Arg/Arg (40% and 54.45%); Gln/Gln (19% and 9.90%),and Arg/Gln (41.0% and 35.64%) respectively. Among these 3 genotypes, we found Gln/Gln and Arg/Gln toshow association with lung cancer. Correlating these genotypes with several parameters, we also found that thesetwo variants were associated with risk in males (p<0.05) and with smoking habits (p<0.05). In females Arg/Glngenotype showed association with stage of the disease (p=0.04). This is the first report in South Indian scenariowhere Arg399Gln genotypes were found to be associated with stage of the disease in females. Conclusions: Itis concluded that XRCC1 genotypes Gln/Gln and Arg/Gln may influence cancer susceptibility in patients withsmoking habits and these functional SNPs in XRCC1 gene may act as attractive candidate biomarkers in lungcancer for diagnosis and prognosis. 相似文献
7.
Zhai X Liu J Hu Z Wang S Qing J Wang X Jin G Gao J Wang X Shen H 《Oncology reports》2006,15(1):247-252
Adenosine diphosphate ribosyl transferase (ADPRT) and X-ray repair cross-complementing 1 (XRCC1) are two major base excision repair (BER) proteins and act cooperatively in the BER processes. Polymorphisms of ADPRT Val762Ala and XRCC1 Arg399Gln may alter their protein functions and BER activity, and were therefore hypothesized to be associated with breast cancer susceptibility. We examined the contributions of these two polymorphisms to breast cancer susceptibility in a case-control study of 302 breast cancer cases, 221 patients with benign breast disease (BBD) and 639 cancer-free controls in a Chinese population. We found that the variant genotypes of both ADPRT Val762Ala and XRCC1 Arg399Gln were not significantly associated with the risk of breast cancer (adjusted OR 0.87, 95% CI 0.64 to 1.19 for ADPRT Val/Ala + Ala/Ala; adjusted OR 0.82, 95% CI 0.61 to 1.11 for XRCC1 Arg/Gln + Gln/Gln; and adjusted OR 0.70, 95% CI 0.45 to 1.10 for these two combined variant genotypes. Similarly, we did not find any significant associations of these two genotypes with BBD risk. These findings suggest that the ADPRT Val762Ala and XRCC1 Arg399Gln polymorphisms may not play a role in the etiology of breast cancer. 相似文献
8.
XRCC1 polymorphisms and head and neck cancer 总被引:12,自引:0,他引:12
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. 相似文献
9.
X-ray repair cross-complementing gene 1 (XRCC1) is involved in base excision repair (BER) through interaction with other BER enzymes, and polymorphisms in XRCC1 appear to increase the risk of various cancers. We evaluated how three XRCC1 polymorphisms, Arg194Trp, Arg280His and Arg399Gln, affect the extent of DNA damage and repair using the micronucleus assay. XRCC1 cDNAs containing the wild-type sequence and the three polymorphisms were overexpressed in EM9 cells, which lack the full sequence needed to perform XRCC1 functions. Normal human XRCC1 cDNA corrected the defect in EM9 cells. Only XRCC1 cDNA containing the Arg399Gln polymorphism did not fully correct the DNA repair defect in EM9 cells. These results indicate that the Arg399Gln polymorphism, but not the Arg194Trp or Arg280His polymorphism, influences the ability of XRCC1 to repair DNA. This study may provide a model that can be used to evaluate the functional significance of polymorphisms in DNA repair genes. 相似文献
10.
A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. 总被引:4,自引:0,他引:4
Xiao-Ou Shu Qiuyin Cai Yu-Tang Gao Wanqing Wen Fan Jin Wei Zheng 《Cancer epidemiology, biomarkers & prevention》2003,12(12):1462-1467
XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA base damage and strand breaks. A common polymorphism (Arg-->Gln) at codon 399 of the XRCC1 gene has been previously linked to functional changes of the gene product and risk of cancers. We evaluated the association between XRCC1 Arg399Gln polymorphism and breast cancer risk in the population-based Shanghai Breast Cancer Study involving 1088 cancer patients and 1182 community controls. Genomic DNA from peripheral blood was used in genotyping assays, and exposure information and anthropometrics were collected through in-person interview. Plasma estrogen and sex hormone-binding globulin (SHBG) levels were measured for 190 postmenopausal breast cancer patients who had donated a pretreatment blood sample and 407 postmenopausal controls. Conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting potential confounders. Approximately 27% of controls carried the variant allele (Gln), and cases and controls had a similar distribution for both allele type and genotype of this polymorphism. We found that 7.8% of cases and 6.3% of controls were homozygous for the variant allele, resulting in an OR of 1.20 (95% CI, 0.85-1.69). The OR was slightly higher among younger women [<45 years of age (OR, 1.39; 95% CI, 0.82-2.36)] than older women [> or = 45 years of age (OR, 1.07; 95% CI, 0.68-1.67)], but neither OR was statistically significant. No modifying effect of major breast cancer risk factors, including years of menstruation, body mass index, waist:hip ratio, and blood estrogen levels, was noted. Homozygosity for the variant Gln allele was associated with an elevated risk of postmenopausal breast cancer among subjects with a higher blood level of SHBG (OR, 3.27; 95% CI, 1.16-9.20) and a reduced risk among those with a lower level of SHBG (OR, 0.60; 95% CI, 0.18-1.97). The overall results of the study suggest that Arg399Gln polymorphism of the XRCC1 gene alone may not play a substantial role in the risk of breast cancer among Chinese women. 相似文献
11.
Endometrial cancer belongs to the commonest malignancy in females. Its development may be associated with the high exposure of endometrium to exo- and endogenous estrogens. Estrogens produce DNA bulky adducts and oxidative base damages which are removed in nucleotide excision repair (NER) and base excision repair (BER) pathways. The reaction of endometrial cells to DNA damage may be crucial for their susceptibility to cancer transformation. This reaction is executed mainly by DNA repair, which can be modulated by the variability in the genes encoding DNA repair proteins. In this report we genotyped 4 polymorphisms of 3 DNA repair genes in 94 endometrial cancer patients and 114 age-matched cancer-free women using RFLP-PCR. The following polymorphisms were studied: p.Arg194Trp, p.Arg399Gln of the XRCC1 gene, p.Ser326Cys of the hOGG1 gene and p.Lys751Gln of the ERCC2 gene. We found an association between the ERCC2 751Gln variant and endometrial cancer occurrence (OR 3.95; 95?% CI 1.88-8.31). Gene-gene interaction between the ERCC2 751Gln and XRCC1 194Trp variants also increased the risk of endometrial cancer (OR 4.41; 95?% CI 2.01-9.67). The risk in the carriers of the ERCC2 751Gln variant was increased by a positive cancer history in first degree relatives (OR 4.97; 95?% CI 1.98-12.48). The risk of endometrial cancer was not alter by polymorphism p.Ser326Cys of the hOGG1 gene. The 751 Lys/Gln polymorphism of the ERCC2 gene may be linked with endometrial cancer occurrence and its effect can be potentiated by variants of the XRCC1 gene or first degree relatives positive cancer history. 相似文献
12.
Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. 总被引:15,自引:0,他引:15
Wei Zhou Geoffrey Liu David P Miller Sally W Thurston Li Lian Xu John C Wain Thomas J Lynch Li Su David C Christiani 《Cancer epidemiology, biomarkers & prevention》2003,12(4):359-365
XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms (Asp312Asn and Lys751Gln) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was 1.3 [95% confidence interval (CI), 1.0-1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2-5.0), whereas for heavy smokers (>/=55 pack-years), the OR decreased to 0.5 (95% CI, 0.3-1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7-16.6) for nonsmokers and 0.3 (95% CI, 0.1-0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk. 相似文献
13.
Yi Li Yi Huang Yu-Shu Cao Jia Zeng Wan-Ning Tong Shi-Lin Xu An-Shan Zhuo 《Tumour biology》2013,34(6):3681-3685
X-ray repair cross-complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base excision repair and plays an important role in the maintenance of genomic integrity. Polymorphisms in XRCC1 may alter the function and repair capacity of XRCC1 protein which further results in the genetic instability and lung carcinogenesis. Previous studies investigating the relationship between XRCC1 Arg399Gln polymorphism and lung cancer risk in Chinese yielded contradictory results. A meta-analysis was performed to clarify the effect of XRCC1 Arg399Gln polymorphism on lung cancer. The association was assessed by calculating the pooled odds ratio (OR) with 95 % confidence intervals (95 %CI). Nineteen studies with a total of 12,835 participants were included into this meta-analysis. Overall, there was an obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer under three genetic models (Gln vs. Arg: OR?=?1.13, 95 %CI 1.01–1.25, P?=?0.029; GlnGln vs. ArArg: OR?=?1.41, 95 %CI 1.07–1.84, P?=?0.013; GlnGln vs. ArArg/ArgGln: OR?=?1.37, 95 %CI 1.07–1.76, P?=?0.013). Meta-analysis of 18 studies with high quality also found that there was an obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer under three genetic models. There was no obvious risk of bias in the meta-analysis. Data from the current meta-analysis support the obvious association between XRCC1 Arg399Gln polymorphism and increased risk of lung cancer in Chinese. 相似文献
14.
Silva SN Moita R Azevedo AP Gouveia R Manita I Pina JE Rueff J Gaspar J 《Cancer Detection and Prevention》2007,31(4):303-309
BACKGROUND: Recent evidence that some DNA-repair functions are haploinsufficient adds weight to the notion that variants in DNA-repair genes constitute part of the spectrum of defects contributing to cancer risk. X-ray repair cross-complementing group 1 gene (XRCC1) is involved in base excision repair (BER) pathway, acting on spontaneous and induced DNA damage. This gene encodes for a scaffolding protein that brings together different proteins involved in the repair process. Among the non-synonymous polymorphisms in XRCC1 gene, codons 194 and 399 lead to amino acid changes at evolutionary conserved regions, and seem to alter the efficiency of the protein. METHODS: A hospital based case-control study was carried out in a Caucasian Portuguese population (241 cancer patients and 457 controls matched for sex and age) in order to evaluate the potential modifying role of the XRCC1 polymorphisms on the individual susceptibility to breast cancer. RESULTS: Our data did not reveal a positive association between the polymorphisms individually and breast cancer, or with the combination of the different genotypic associations. However, after stratification to the menopausal status, it was observed that carriers of the Gln/Gln genotype of the R399Q polymorphism with a menopausal age above 55 years are at increased risk for breast cancer (OR=4.074; CI=1.562-10.626; P=0.004). Concerning the Arg194Trp polymorphism, after stratification by menopausal status, it was observed that heterozygous individuals (Arg/Trp) with a menopausal age between 45 and 54 are at increased risk for breast cancer (adjusted OR=1.964; CI=1.174-3.288; P=0.01) as well as carriers of the variant allele (Arg/Trp+Trp/Trp) (adjusted OR=1.932; CI=1.156-3.228; P=0.012). CONCLUSIONS: Our results suggest that menopausal age together with Arg194Trp and Arg399Gln XRCC1 gene polymorphisms might be involved in individual susceptibility to breast cancer. 相似文献
15.
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. 相似文献
16.
Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma 总被引:9,自引:0,他引:9
To test the hypothesis that aberrations of DNA repair contribute to susceptibility for the progression of gastroesophageal reflux disease (GERD) into Barrett esophagus (BE) and esophageal adenocarcinoma (EADC), we studied the frequency of polymorphisms of selected DNA repair genes in patients with GERD (n = 126), BE (n = 125) and EADC (n = 56) enrolled in a 2-year prospective case-control study. Controls comprised 95 strictly asymptomatic healthy individuals. Using genomic DNA extracted from blood samples, we identified wild-type and polymorphic variants of XPD (Arg156Arg and Lys751Gln), XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met), and the poly (AT) insertion/deletion of XPC (PAT). Allelic frequencies were compared between cases and controls using logistic regression to calculate age, gender, smoking and alcohol-adjusted odds ratios (OR) and 95% confidence intervals (CI). Patients with EADC demonstrated a significantly higher frequency of the XPC PAT homozygous variant genotype compared with asymptomatic controls (OR = 3.82; 95% CI = 1.05-13.93). Significantly reduced frequencies were seen for the XPD Lys751Gln homozygous variant genotype in patients with EADC (OR = 0.24; 95% CI = 0.07-0.88), and for the XRCC1 Arg399Gln homozygous variant genotype in patients with BE (OR = 0.38; 95% CI = 0.12-0.64) and GERD (OR = 0.29; 95% CI = 0.12-0.66). We conclude that the malignant phenotype probably results from a summation of polymorphic nucleotide excision repair genes showing opposing effects (an increased risk of XPC versus a protective effect of XPD). The protective effect of the homozygous variant of XRCC1 Arg399Gln for GERD and BE suggests that base excision repair alterations may occur early in progression to EADC, likely in response to GERD-induced endogenous oxidative or inflammatory DNA damage. As GERD and BE are highly prevalent in the general population, this protective effect may well explain why only a fraction of individuals with GERD and BE progress into invasive EADC. 相似文献
17.
The XRCC1 399Gln polymorphism and the frequency of p53 mutations in Taiwanese oral squamous cell carcinomas. 总被引:4,自引:0,他引:4
Ling-Ling Hsieh Huei-Tzu Chien I-How Chen Chun-Ta Liao Hung-Ming Wang Shih-Ming Jung Pei-Feng Wang Joseph Tung-Chieh Chang Min-Chi Chen Ann-Joy Cheng 《Cancer epidemiology, biomarkers & prevention》2003,12(5):439-443
DNA repair gene polymorphisms have been implicated as susceptibility factors in cancer development. It is possible that DNA repair polymorphisms may also influence the risk of gene mutation. The 399Gln polymorphism in the DNA repair gene XRCC1 has been indicated to have a contributive role in DNA adduct formation, sister chromatid exchange, and an increased risk of cancer development. Two hundred thirty-seven male oral squamous cell carcinomas (OSCCs) were included in a study to investigate the role of the XRCC1 194Trp, 280His, and 399Gln polymorphisms on p53 gene mutation. PCR-single-strand conformation polymorphism and DNA sequencing were used to analyze the conserved regions of the p53 gene (exons 5-9). The XRCC1 genotype was determined by PCR-RFLP. Nineteen (8.02%) of the 237 OSCCs had a Gln/Gln genotype. One hundred six (43.88%) of the 237 OSCCs showed p53 gene mutations at exons 5-9. The OSCC patients with a Gln/Gln genotype exhibited a significantly higher frequency of p53 mutation than those with an Arg/Gln and an Arg/Arg genotype. After adjustment for age, cigarette smoking, areca quid chewing, and alcohol drinking, the Gln/Gln genotype still showed an independent association with the frequency of p53 mutation (odd ratio, 4.50; 95% confidence interval, 1.52-13.36). The findings support the hypothesis that XRCC1 Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in a DNA repair deficiency. This study also suggests an important role for the XRCC1 399Gln polymorphism in p53 gene mutation in Taiwanese OSCCs. 相似文献
18.
Polymorphisms of DNA repair genes and risk of non-small cell lung cancer 总被引:24,自引:0,他引:24
Zienolddiny S Campa D Lind H Ryberg D Skaug V Stangeland L Phillips DH Canzian F Haugen A 《Carcinogenesis》2006,27(3):560-567
Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean. 相似文献
19.
目的研究广西扶绥县肝癌家系人群DNA修复基因XRCC1Arg399Gln多态性与肝细胞癌(HCC)遗传易感性的相关性。方法采用病例-对照研究方法,对扶绥县21个肝癌家系人群和10个正常家系人群,运用PCR-RFLP方法分析XRCC1基因Arg399Gln位点多态性,并应用Logistic回归模型分析该位点多态性与肝细胞癌遗传易感性的关系。结果通过XRCC1Arg399Gln基因型检测分型,肝癌家系人群携带变异等位基因Gln的频率为23.68%,正常家系人群为13.16%,等位基因在两组间的分布差异无统计学意义(P〉0.05)。基因型分布符合Hardy-Weinberg平衡定律。正常家系人群中携带Arg/Gln者发生HCC的风险是携带Arg/Arg者的1.622倍(95%CI=0.475~5.541,P=0.440)。肝癌家系人群中除肝癌患者外,携带Arg/Gln、Gln/Gln者发生HCC的风险分别是携带Arg/Arg者的1.198倍(95%CI=0.362~3.968)和2.964倍(95%CI=0.434~20.220,P分别为0.768、0.267)。结论广西扶绥县肝癌家系人群中,XRCC1399Arg/Gln基因型和Gln/Gln基因型者患HCC的风险较Arg/Arg基因型者有增加的趋势,但不存在显著相关性。 相似文献
20.
Li M Yin Z Guan P Li X Cui Z Zhang J Bai W He Q Zhou B 《Lung cancer (Amsterdam, Netherlands)》2008,62(2):145-151
X-ray repair cross-complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base excision repair (BER) and single-strand break repair (SSBR) pathway. Single nucleotide polymorphisms (SNPs) in XRCC1 may alter protein function and repair capacity, thus lead to genetic instability and carcinogenesis. To establish our understanding of possible relationships between XRCC1 polymorphisms (5'UTR -77T>C, Arg194Trp, Arg280His and Arg399Gln) and the susceptibility to lung cancer among women nonsmokers, we performed a hospital-based case-control study of 350 patients with newly diagnosed lung cancer and 350 cancer-free controls, frequency matched by age. Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese women nonsmokers [odds ratio (OR)=2.51, 95% confidence interval (CI) [1.80-3.51], P<0.001]. Individuals with homozygous XRCC1 399Gln/Gln genotype (OR=1.75, 95% CI [1.02-3.01]) and XRCC1 -77 combined TC and CC genotype (OR=1.66, 95% CI [1.13-2.42]) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals with homozygous XRCC1 399Gln/Gln genotype (OR=2.62, 95% CI [1.44-4.79]) and XRCC1 -77 combined TC and CC genotype (OR=1.85, 95% CI [1.19-2.86]). Haplotype analysis showed that T-Trp-Arg-Gln haplotypes were associated with an increased risk of lung cancer among women nonsmokers (OR=2.26, 95% CI [1.38-3.68]), however, we did not observe a statistically significant joint effect of cooking oil fume and 399Gln or -77C variant allele on lung cancer among women nonsmokers. In conclusion, XRCC1 Arg399Gln and T-77C polymorphisms may alter the risk of lung cancer in women nonsmokers in China. 相似文献