Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.

PURPOSE: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. EXPERIMENTAL DESIGN: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. RESULTS: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. CONCLUSION: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.     

Implication of Polymorphisms in DNA Repair Genes in Prognosis of Hepatocellular Carcinoma

XRCC1 genetic polymorphisms could be associated with increased risk of various cancer, includinghepatocellular carcinoma (HCC), the fifth most common cancer. We here conducted a study to explore the roleof selective SNPs of the XRCC1 and XPD genes in the prognosis of HCC. A total of 231 cases were collected, andgenotyping of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Asn was performedby duplex polymerase-chain-reaction with the confronting-two-pair primer method. Our findings indicatedXRCC1 399Gln/Gln genotype was associated with a significant difference in the median survival time comparedwith patients carrying Arg/Trp and Arg/Arg genotypes, and individuals with XPD 751 Gln/ Gln genotype had asignificantly greater survival time than patients carrying Lys/Lys and Lys/Gln genotypes. The Cox’s regressionanalysis showed individuals carrying XRCC1 399Trp/Trp genotype had 0.55 fold risk of death from HCC thanArg/Arg genotype. Similarly, XPD 751Gln/Gln had a strong decreasein comparison to XPD Lys/Lys carriers withan HR of 0.34. These results suggest that polymorphisms in XRCC1 and XPD may have functional significancein the prognosis of HCC.     

Distribution and Haplotype Associations of XPD Lys751Gln,XRCC1 Arg280His and XRCC1 Arg399Gln Polymorphisms with Nasopharyngeal Carcinoma in the Malaysian Population

Background: DNA repair pathways play a crucial role in maintaining the human genome. Previous studiesassociated DNA repair gene polymorphisms (XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln)with nasopharyngeal carcinoma. These non-synonymous polymorphisms may alter DNA repair capacity andthus increase or decrease susceptibility. The present study aimed to determine the genotype distribution of XPDcodon 751, XRCC1 codon 280 and codon 399 polymorphisms and haplotype associations among NPC cases andcontrols in the Malaysian population. Materials and Methods: We selected 157 NPC cases and 136 controls fromtwo hospitals in Kuala Lumpur, Malaysia for this study. The polymorphisms studied were genotyped by PCRRFLPassay and allele and genotype frequencies, haplotype and linkage disequilibrium were determined usingSNPstat software. Results: For the XPD Lys751Gln polymorphism, the frequency of the Lys allele was higher incases than in controls (94.5% versus 85.0%). For the XRCC1 Arg280His polymorphism, the frequency of Argallele was 90.0% and 89.0% in cases and controls, respectively and for XRCC1 Arg399Gln the frequency of theArg allele was 72.0% and 72.8% in cases and controls respectively. All three polymorphisms were in linkagedisequilibrium. The odds ratio from haplotype analysis for these three polymorphisms and their associationwith NPC was 1.93 (95%CI: 0.90-4.16) for haplotype CGC vs AGC allele combinations. The global haplotypteassociation with NPC gave a p-value of 0.054. Conclusions: Our study provides an estimate of allele and genotypefrequencies of XRCC1Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in the Malaysianpopulation and showed no association with nasopharyngeal cancer.     

MS-920: DNA repair gene polymorphisms, diet and colorectal cancer risk in Taiwan

This hospital-based case-control study examined whether polymorphic DNA repair genes: XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, play a role in the susceptibility to colorectal cancer. We genotyped these polymorphisms for 727 newly diagnosed colorectal adenocarcinoma cases and 736 age and sex matched healthy controls in Taiwan. Although the colorectal cancer risk was not significantly associated with these genes, the risk was significantly elevated in younger subjects (< or =60 years) with the XRCC1 399Arg/Arg genotype compared to those with XRCC1 399Gln allele (OR=1.46, 95% CI=1.06-2.99, P=0.02). The stratified analysis showed that XRCC3 interacted with meat consumption (P for interaction=0.02), but was limited to the low meat consumption (OR=2.34, 95% CI=1.28-4.29). Our results suggest that the XRCC1 Arg399Gln polymorphism may contribute to the risk of early-onset colorectal cancer and the XRCC3 Thr241Met polymorphism may modify the risk for meat-associated colorectal cancer.     

Polymorphisms of DNA repair genes XRCC1 and XPD and their associations with risk of esophageal squamous cell carcinoma in a Chinese population

Esophageal squamous cell carcinoma (ESCC), which is prevalent in China, is believed to be induced by environmental carcinogens. Accumulating evidence has shown that individual variation in DNA repair capacity resulting from genetic polymorphism influences risk of environmental carcinogenesis. We therefore investigated the associations between genetic polymorphisms in the DNA repair genes XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) and risk of ESCC in an at-risk Chinese population. Genotypes were determined by a PCR-based approach in 433 patients with ESCC and 524 frequency-matched normal controls. We found that individuals with Trp/Trp genotype at XRCC1 Arg194Trp site had a 2-fold increased risk of this disease compared to Arg/Arg genotype (adjusted OR = 1.98; 95% CI 1.26-3.12). Furthermore, when compared to Arg/Arg and Arg/Trp genotype combined, homozygote for Trp/Trp genotype significantly increased the risk of developing ESCC, with the adjusted OR being 2.07 (95% CI 1.34-3.20). However, the XRCC1 Arg399Gln polymorphism was not significantly associated with risk of ESCC, with the adjusted OR being 0.87 (95% CI 0.55-1.37). Neither Asp312Asn nor Lys751Gln polymorphisms in the XPD gene influenced risk of ESCC in our study. These findings suggest that DNA repair gene XRCC1 but not XPD might play a role in esophageal carcinogenesis and might represent a genetic determinant in the development of the cancer.     

XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk.

Using a sigmoidoscopy-based case-control study (753 cases, 799 controls) in Los Angeles County, we investigated the potential modifier role in the effect of alcohol and smoking of single-nucleotide polymorphisms (SNP) in three DNA repair genes, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and XPD (Lys751Gln). We have previously reported an inverse association between the XRCC1 codon 399 SNP and adenoma risk among these subjects. We now report that subjects with the XPD Gln/Gln genotype were inversely associated with adenoma risk [odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-1.0] when compared with subjects with the Lys/Lys and Lys/Gln genotypes combined. This association differed between different ethnic groups (gene x race heterogeneity likelihood ratio test, P = 0.009), with a stronger inverse association among Latinos (OR, 0.1; 95% CI, 0.01-0.5) than among non-Latinos (OR, 0.9; 95% CI, 0.-1.3). We found no evidence of an XRCC3 x smoking or alcohol interaction or an XRCC1 x alcohol interaction. Instead, our data supported an XRCC1 x smoking interaction (P = 0.048). Whereas XPD did not modify the effect of smoking, our data suggested an XPD x alcohol interaction. Analyses ignoring XPD showed no association between alcohol intake and adenoma prevalence; however, among carriers of the codon 751 Gln/Gln genotype, we found a significant positive association (OR, 2.5; 95% CI, 1.2-5.2 for ever drinkers; test of interaction P = 0.04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways.     

Lack of Influence of XRCC1 and XPD Gene Polymorphisms on Outcome of Platinum-based Chemotherapy for Advanced Non Small Cell Lung Cancers

Purpose: Genetic polymorphisms of DNA repair genes are associated with differential enzyme activity andmay help explain interindividual differences in response rates after platinum-based chemotherapy for non smallcell lung cancers (NSCLCs). This study was conducted to assess relationships between X-ray repair crosscomplementing group1 (XRCC1) and xeroderma pigmentosum group D (XPD) genetic polymorphisms andoutcome in NSCLC patients. Methods: From March 1, 2005 to December 31, 2008, the polymerase chainreaction-restriction fragment length polymorphism method was applied to evaluate genetic polymorphisms ofthe XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) DNA repair genes in 108 patients with stage IIIBand IV NSCLCs treated with platinum-based chemotherapy in the Department of Chemotherapy of JiangsuCancer Hospital and Research Institute. Results: Among the assessed NSCLC patients, the overall responserate of chemotherapy was 21.6%. No association was found with either of the genetic polymorphisms, althoughthe XRCC1 399Arg/Arg genotype was associated with a non-significant higher median survival time (29 monthsversus 21 months for the Arg/Gln genotype and 15 months for the Gln/Gln genotype, P=0.09). Conclusion: Ourresults suggested no influence of the XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) geneticpolymorphisms on treatment response and survival in advanced NSCLC patients with platinum-basedchemotherapy.     

Association of XPD and XRCC1 Genetic Polymorphisms with Hepatocellular Carcinoma Risk

Aim: XRCC1 and XPD are two major repair genes involved in nucleotide excision repair (NER), whichis reported to be associated with risk of several cancers. We explored the association of XRCC1 and XPDpolymorphisms with the risk of HCC. Methods: A total of 410 cases with HCC and 410 health controls werecollected. XRCC1 Arg194Trp, XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Asn genotyping wasperformed by duplex polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method.Results: XRCC1 194Trp/Trp was strongly significantly associated with an increased risk of HCC cancer whencompared with the wide-type genotype (OR=2.26, 95% CI=(1.23-5.38). Individuals carrying the XRCC1 399Gln/Gln showed increased risk of HCC (OR=1.74, 95%CI=1.06-2.74). The XPD 751Gln/Gln and Gln allele genotypewere associated with strong elevated susceptibility to HCC (OR=3.51 and 1.42, respectively). Conclusion: Theseresults suggest that polymorphisms in XRCC1 and XPD may have functional significance in risk of HCC.     

Interaction of XRCC1 and XPD Gene Polymorphisms with Lifestyle and Environmental Factors Regarding Susceptibility to Lung Cancer in a High Incidence Population in North East India

Background: This study aimed to explore the role of XRCC1 (Arg399Gln) and XPD (Lys751Gln) genepolymorphisms, lifestyle and environmental factors as well as their possible interactions in propensity to developlung cancer in a population with high incidence from North East India. Materials and Methods: A total of 272lung cancer cases and 544 controls were collected and XRCC1 (Arg399Gln) and XPD (Lys751Gln) genotypes wereanalyzed using a polymerase chain reaction based restriction fragment length polymorphism assay. Conditionalmultiple logistic regression analysis was used to calculate adjusted odds ratios and 95% confidence intervalsafter adjusting for confounding factors. Results: The combined Gln/Gln genotype of XRCC1 and XPD genes(OR=2.78, CI=1.05-7.38; p=0.040) was significantly associated with increased risk for lung cancer. Interactionof XRCC1Gln/Gln genotype with exposure of wood combustion (OR=2.56, CI=1.16-5.66; p=0.020), exposure ofcooking oil fumes (OR=3.45, CI=1.39-8.58; p=0.008) and tobacco smoking (OR=2.54, CI=1.21-5.32; p=0.014) andinteraction of XPD with betel quid chewing (OR=2.31, CI=1.23-4.32; p=0.009) and tobacco smoking (OR=2.13,CI=1.12-4.05; p=0.022) were found to be significantly associated with increased risk for lung cancer. Conclusions:Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smokingand betel quid chewing on lung cancer risk in the study population.     

食管癌中ERCC2/XPD和XRCC1基因多态性的表达

目的:探讨DNA损伤修复基因ERCC2/XPD和XRCC1基因多态性与食管癌遗传易感性的关系。方法:采用病例对照研究设计,选取100例食管癌病例和80例正常对照。选取ERCC2/XPD Lys751Gln和XRCC1 Arg399Gln基因多态性为研究位点,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法进行多态性检测,应用Logistic回归计算OR值及95%CI,比较不同基因型与食管癌发病风险的关系。结果:病例组和对照组中变异型等位基因ERCC2/XPD Lys751Gln的频率分别是15.7%和13.0%。与野生基因型Lys/Lys相比,携带XPD Lys/Gln和Gln/Gln基因型者患食管癌的危险度比值比(odds ratio,OR)分别是1.94(95%CI:1.22～3.36)和0.56（95%CI:0.15～2.64)。变异型等位基因XRCC1 399Gln的频率在病例组和对照组中分别是29.8%和30.2%,与野生基因型XRCC1 Arg/Arg相比,带Arg/Gln和Gln/Gln基因型者患食管癌的OR分别是0.94(95%CI:0.69～1.31)和1.83(95%CI:0.84～3.89)。分析结果提示饮酒、酸泡菜与XPD Lys751Gln基因多态存在交互作用,交互效应OR值分别为2.24(95%CI:1.18～2.87)和2.53(95%CI:1.71～3.46),携带XPD Lys751Gln和XRCC Arg1399Gln突变基因者若同时暴露于酸泡菜或酒精,则患食管癌的危险显著增加,相较未暴露于上述因素者,OR值均增大。结论:DNA损伤修复基因ERCC2/XPD和XRCC1单核苷酸多态性可能与当地居民食管癌遗传易感性有关,与饮酒、酸泡菜存在交互作用。     

Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma

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.     

Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer

Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.     

DNA损伤修复基因XRCC1和XPD遗传多态与晚期非小细胞肺癌对铂类药物的敏感性

目的 探讨DNA损伤修复基因XRCC1和XPD的遗传多态与晚期非小细胞肺癌（NSCLC）对以铂类为主化疗药物敏感性的关系。方法 以聚合酶链反应（PCR）结合限制性片段长度多态性（RFLP）,检测200例以顺铂（DDP）或卡铂（CBP）为主要化疗方案的NSCLC患者XRCC1 Arg194Trp和XPD Lys751Gln多态基因型,并比较不同基因型与化疗敏感性的关系。结果 化疗总有效（CR＋PR）率为36．0％,其中CR1例,PR71例,SD94例,PD34例。携带XRCC1第194位密码子Arg／Trp或Trp／Trp基因型的个体化疗敏感性是XRCC1第194位密码子Arg／Arg基因型携带者的2．48倍（95％CI为1．36～4．51,P=0．003）;未发现XPD Lys751Gln多态与化疗敏感性的相关性。联合分析这两个遗传多态发现,XRCC1 Arg194Trp和XPD Lys751Gln多态在NSCLC对铂类药物敏感性中存在一定的联合作用（趋势检验,P=0．004）。结论XRCC1 Arg194Trp和XPDLys751Gin遗传多态可能与NSCLC铂类药物敏感性有关。     

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

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.     

DNA Repair Gene Associated with Clinical Outcome ofEpithelial Ovarian Cancer Treated with Platinum-basedChemotherapy

Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repairpathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association betweensingle nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy inepithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques.Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Glngenotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overallsurvival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox’s multivariate analysis suggestedthat patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95%CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-,XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survivalof patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Ourresults indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients withepithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.     

DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer.

The X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genes are involved in base excision repair and nucleotide excision repair of DNA repair pathways, respectively. A growing body of evidence suggests that XRCC1 and XPD are important in environmentally induced cancers, and polymorphisms in both genes have been identified. To determine whether the XRCC1 (codon Arg399Gln) and XPD (codon Asp312Asn and codon Lys751Gln) polymorphisms are associated with prostate cancer susceptibility, we genotyped these polymorphisms in a primarily Caucasian sample of 506 sibships (n = 1,117) ascertained through a brother with prostate cancer. Sibships were analyzed with a Cox proportional hazards model with age at prostate cancer diagnosis as the outcome. Of the three polymorphisms investigated, only the XPD codon 312 Asn/Asn genotype had an odds ratio (OR) significantly different from one (OR, 1.61; 95% CI, 1.03-2.53). Analyses stratified by the clinical characteristics of affected brothers in the sibship did not reveal any significant heterogeneity in risk. In exploring two-way gene interactions, we found a markedly elevated risk for the combination of the XPD codon 312 Asn/Asn and XRCC1 codon 399 Gln/Gln genotypes (OR, 4.81; 95% CI, 1.66-13.97). In summary, our results suggest that the XPD codon 312 Asn allele may exert a modest positive effect on prostate cancer risk when two copies of the allele are present, and this effect is enhanced by the XRCC codon 399 Gln allele in its recessive state.     

DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study.

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.     

XPD Lys751Gln多态性与成年人急性白血病发病风险的关系研究

目的 探讨核苷酸切除修复基因XPD Lys751Gln多态性与成年人急性白血病(AL)发病风险的关系.方法 按照1∶1配对病例对照研究方法,选择100例成年人AL患者为病例组,100名健康体检人群为对照组,采用聚合酶链反应-限制性片段长度多态性方法检测观察对象外周血XPDLys751Gln基因多态性.结果 成年人AL病例组和对照组Lys/Lys、Lys/Gln、Gln/Gln基因型分布频率分别为83%、16%、1%和90%、10%、0,两组比较差异无统计学意义(x2=1.44,P=0.49);携带XPDLys751Gln突变基因(Lys/Gln+Gln/Gln)的个体不增加AL的发病风险(x2=2.10,P=0.15,OR=1.84;95%CI0.80～4.25).按FAB形态学分型,携带XPD Lys751 Gln突变基因型(Lyg/Gln+Gln/Gln)个体患AL的危险度增加(OR=2.77,95%CI0.99～7.73).结论 XPD Lys751Gln可能与成年人急性淋巴细胞白血病的发病风险有关.     

XPD Lys751Gln多态性与成年人急性白血病发病风险的关系研究

 目的　探讨核苷酸切除修复基因XPD Lys751Gln多态性与成年人急性白血病（AL）发病风险的关系。方法　按照1∶1配对病例对照研究方法,选择100例成年人AL患者为病例组,100名健康体检人群为对照组,采用聚合酶链反应-限制性片段长度多态性方法检测观察对象外周血XPD Lys751Gln基因多态性。结果　成年人AL病例组和对照组Lys／Lys、Lys／Gln、Gln／Gln基因型分布频率分别为83 %、16 %、1 %和90 %、10 %、0,两组比较差异无统计学意义（χ2＝1.44,P＝0.49）;携带XPD Lys751Gln突变基因（Lys／Gln+Gln／Gln）的个体不增加AL的发病风险（χ2＝2.10,P＝0.15,OR＝1.84;95 % CI 0.80～4.25）。按FAB形态学分型,携带XPD Lys751Gln突变基因型（Lys／Gln+ Gln／Gln）个体患AL的危险度增加（OR＝2.77,95 % CI 0.99～7.73）。结论　XPD Lys751Gln可能与成年人急性淋巴细胞白血病的发病风险有关。     

DNA repair gene polymorphism associated with sensitivity of lung cancer to therapy

This study aimed to investigate association between single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing gene 1 (ERCC1), excision repair cross-complementing gene 2 (ERCC2), and X-ray repair cross-complementing group 1 (XRCC1) with sensitivity of advanced non-small cell lung cancer (NSCLC) patients to platinum-based chemotherapy. A total of 89 NSCLC patients were recruited and treated with two cycles of platinum-based chemotherapy. DNA was extracted from peripheral lymphocytes for detection of SNPs of ERCC1 Asn118Asn, ERCC2 Lys751Gln, and XRCC1 Arg399Gln. The overall response rate of these patients was 29.2%. There was no statistically significant difference of treatment response between the wild genotypes and the variant genotypes for the ERCC1 Asn118Asn and ERCC2 Lys751Gln gene. The distributions of genotypes XRCC1 Arg399Gln differed significantly between the response and non-response groups (76.9 vs. 23.1%, P = 0.001). The XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95%CI = 1.778-13.013, P = 0.002). The combination of the favorable genotypes of ERCC1, ERCC2, and XRCC1 had a higher response rate compared to that of patients with other genotypes. The combined polymorphisms of ERCC1, ERCC2, and XRCC1 may be associated with sensitivity of NSCLC to platinum-based chemotherapy. Further studies will verify these SNPs as biomarkers for prediction of platinum-based chemotherapy responses of NSCLC patients.