Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk.

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3'-untranslated region 8092C/A), XPA (5'-untranslated region -4G/A), XPD (Asp(312)Asn in exon 10), XPF (Arg(415)Gln in exon 8), and XPG (Asp(1104)His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts.     

Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer

Several polymorphisms in DNA repair genes have been reported to be associated with lung cancer risk including XPA (-4G/A), XPD (Lys751Gln and Asp312Asn), XRCC1 (Arg399Gln), APE1 (Asp148Glu) and XRCC3 (Thr241Met). As there is little information on the combined effects of these variants, polymorphisms were analyzed in a case-control study including 463 lung cancer cases [among them 204 adenocarcinoma and 212 squamous cell carcinoma (SCC)] and 460 tumor-free hospital controls. Odds ratios (OR) adjusted for age, gender, smoking and occupational exposure were calculated for the variants alone and combinations thereof. For homozygous individuals carrying the Glu variant of APE1, a protective effect was found (OR = 0.77, CI = 0.51-1.16). Individuals homozygous for the variants XPA (-4A) (OR = 1.53, CI = 0.94-2.5), XPD 751Gln (OR = 1.39, CI = 0.90-2.14) or XRCC3 241Met (OR = 1.29, CI = 0.85-1.98) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals homozygous for XPA (-4A) (OR = 1.62, CI = 0.91-2.88) and XRCC3 241Met (OR = 1.65; CI = 0.99-2.75). When analyzing the combined effects of variant alleles, 54 patients and controls were identified that were homozygous for two or three of the potential risk alleles [i.e. the variants in nucleotide excision repair, XPA (-4A) and XPD 751Gln, and in homologous recombination, XRCC3-241Met]. ORs were significantly increased when all patients (OR = 2.37; CI = 1.26-4.48), patients with SCC (OR = 2.83; CI = 1.17-6.85) and with adenocarcinoma (OR = 3.05; CI = 1.49-6.23) were analyzed. Combinations of polymorphisms in genes involved in the same repair pathway (XPA + XPD or XRCC1 + APE1) affected lung cancer risk only in patients with SCC. These results indicate that lung cancer risk is only moderately increased by single DNA repair gene variants investigated but it is considerably enhanced by specific combinations of variant alleles. Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high-risk subjects.     

DNA repair gene variants in endometrial carcinoma

Several polymorphisms in the DNA repair gene are thought to have significant effects on cancer risk. In this study, we investigated the association of the polymorphisms in the DNA repair genes, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, and HOGG1 Ser326Cys, with endometrium cancer risk. Two hundred and sixty-two women were included in the study. Endometrial biopsy was performed, and on the basis of diagnosis and histological examination, women were divided into two groups: a control group (n?=?158) and an endometrial cancer group (n?=?104). Genotypes were determined by PCR-RFLP assays in endometrial carcinoma patients and age-matched controls. In this study, we found that the frequencies of Glu+ and Asp/Glu genotypes in APE, Gln/Gln genotype of XRCC1, Met/Met genotype of XRCC3, Cys+ and Ser/Cys genotypes of HOGG1, His+ and Asp/His genotypes of XPG, and Gln+ and Gln/Gln genotypes of XPD are more prevalent in patients than controls. Frequencies of Thr/Thr genotype in XRCC3 were increased in controls compared with patients and seem to be protected from endometrial cancer. Our findings suggest that XRCC1, XRCC3, XPD, XPG, APE1, and HOGG1 genetic variants may be associated with endometrial cancer in Turkish women.     

Association of DNA Base-excision Repair XRCC1, OGG1 and APE1 Gene Polymorphisms with Nasopharyngeal Carcinoma Susceptibility in a Chinese Population

Background: Numerous carcinogens and reactive oxygen species (ROS) may cause DNA damage includingoxidative base lesions that lead to risk of nasopharyngeal carcinoma. Genetic susceptibility has been reported toplay a key role in the development of this disease. The base excision repair (BER) pathway can effectively removeoxidative lesions, maintaining genomic stability and normal expression, with X-ray repair crosscomplementing1(XRCC1), 8-oxoguanine glycosylase-1 (OGG1) and apurinic/apyimidinic endonuclease 1 (APE1) playingimportant roles. Aims: To analyze polymorphisms of DNA BER genes (OOG1, XRCC1 and APE1) and exploretheir associations, and the combined effects of these variants, with risk of nasopharyngeal carcinoma. Materialsand Methods: We detected SNPs of XRCC1 (Arg399Gln), OGG1 (Ser326Cys), APE1 (Asp148Glu and -141T/G)using the polymerase chain reaction (PCR) with peripheral blood samples from 231 patients with NPC and 300healthy people, furtherly analyzing their relations with the risk of NPC in multivariate logistic regression models.Results: After adjustment for sex and age, individuals with the XRCC1 399Gln/Gln (OR=1.96; 95%CI:1.02-3.78; p=0.04) and Arg/Gln (OR=1.87; 95%CI:1.29-2.71; p=0.001) genotype variants demonstrated a significantlyincreased risk of nasopharyngeal carcinoma compared with those having the wild-type Arg/Arg genotype. APE1-141G/G was associated with a significantly reduced risk of NPC (OR=0.40;95%CI:0.18–0.89) in the smokinggroup. The OR calculated for the combination of XRCC1 399Gln and APE1 148Gln, two homozygous variants,was significantly additive for all cases (OR=2.09; 95% CI: 1.27-3.47; p=0.004). Conclusion: This is the first studyto focus on the association between DNA base-excision repair genes (XRCC1, OGG1 and APE1) polymorphismand NPC risk. The XRCC1 Arg399Gln variant genotype is associated with an increased risk of NPC. APE1-141G/G may decrease risk of NPC in current smokers. The combined effects of polymorphisms within BERgenes of XRCC1 399Gln and APE1 148Gln may contribute to a high risk of nasopharyngeal carcinoma.     

Polymorphisms in DNA Repair Genes and Risk of Glioma and Meningioma

Polymorphisms in DNA repair genes have been shown to influence DNA repair processes and to modifycancer susceptibility. Here we conducted a case-control study to assess the role of potential SNPs of DNA repairgenes on the risk of glioma and meningioma. We included 297 cases and 458 cancer-free controls. Genotypingof XRCC1 Gln399Arg, XRCC1 Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met, XRCC4 Ala247Ser,ERCC1 Asn118Asp, ERCC2 Lys751Gln and ERCC5 Asp1558His were performed in a 384-well plate formaton the Sequenom MassARRAY platform. XRCC1 Arg194Trp (rs1799782) and ERCC2 Asp312Asn rs1799793did not follow the HWE in control group, and genotype distributions of XRCC1 Gln399Arg rs25487, XRCC2Arg188His rs3218536 and ERCC2 Asp312Asn rs1799793 were significantly different between cases and controls(P<0.05). We found XRCC1 399G/G, XRCC1 194 T/T and XRCC3 241T/T were associated with a higher riskwhen compared with the wild-type genotype. For ERCC5 Asp1558His, we found G/G genotype was associatedwith elevated susceptibility. In conclusion, our study has shown that XRCC1 Gln399Arg, XRCC1 Arg194Trp,XRCC3 Thr241Met and ERCC5 Asp1558His are associated with risk of gliomas and meningiomas. This findingcould be useful in identifying the susceptibility genes for these cancers.     

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.     

Single Nucleotide Polymorphisms of DNA Base-excision Repair Genes (APE1, OGG1 and XRCC1) Associated with Breast Cancer Risk in a Chinese Population

Altered DNA repair capacity can result in increased susceptibility to cancer. The base excision repair (BER)pathway effectively removes DNA damage caused by ionizing radiation and reactive oxidative species (ROS).In the current study, we analyzed the possible relation of polymorphisms in BER genes, including 8-oxoguanineDNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and X-ray repair cross-complementinggroup 1 protein (XRCC1), with breast cancer risk in Chinese Han women. This case-control study examined 194patients with breast cancer and 245 cancer-free hospitalized control subjects. Single nucleotide polymorphisms(SNPs) of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), and APE1 (Asp148Glu and -141T/G) were genotyped andanalyzed for their association with breast cancer risk using multivariate logistic regression models. We found thatXRCC1 Arg399Gln was significantly associated with an increased risk of breast cancer. Similarly, the XRCC1Gln allele was significantly associated with an elevated risk in postmenopausal women and women with a highBMI (≥ 24 kg/m2). The OGG1 Cys allele provided a significant protective effect against developing cancer inwomen with a low BMI (< 24 kg/m2). When analyzing the combined effects of these alleles on the risk of breastcancer, we found that individuals with ≥ 2 adverse genotypes (XRCC1 399Gln, APE1 148Asp, and OGG1 326Ser)were at a 2.18-fold increased risk of breast cancer (P = 0.027). In conclusion, our data indicate that Chinesewomen with the 399Gln allele of XRCC1 have an increased risk of breast cancer, and the combined effects ofpolymorphisms of BER genes may contribute to tumorigenesis.     

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。     

Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients.

PURPOSE: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy. DESIGN: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009). CONCLUSION: The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.     

Influence of DNA repair gene polymorphisms on prognosis in inoperable non-small cell lung cancer patients treated with radiotherapy and platinum-based chemotherapy

Polymorphisms in DNA repair genes may modulate not only an individual DNA repair capacity, DNA damage levels and cancer risk but also clinical outcome after DNA damage-inducing anticancer therapy. In this study, we analyzed the association between the XPA -4G>A, XPD Asp312Asn, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC2 -4234G>C, XRCC3 -4541A>G and Thr241Met polymorphisms and prognosis in 250 inoperable non-small cell lung cancer (NSCLC) patients treated with radiotherapy and platinum-based chemotherapy. In univariate model, the XPA-4A and XRCC1 399Gln alleles alone and in combination influenced survival only in stage III group. In multivariate analysis, the XPA-4 GA/AA was associated with poor survival (HR 1.55, p = 0.011 overall and HR 1.72, p = 0.008 in stage III). In chemoradiotherapy group, the XPA-4A carriers were at increased risk of death and progression (HR 1.73, p = 0.013 and HR 1.65, p = 0.016, respectively), especially in stage III (p = 0.008). Moreover, individuals with ≥ 2 XPA/XRCC1 adverse alleles showed a higher risk of death (HR 1.46, p = 0.036 overall; HR 1.85, p = 0.004 in stage III and HR 1.71, p = 0.022 in chemoradiotherapy group) and progression (HR 1.75, p = 0.011 overall and HR 1.93, p = 0.005 in stage III). The XPA-4 GA/AA genotype individually and together with the XRCC1 399Gln was an independent unfavorable prognostic factor in our study. Thus, our findings indicate a prognostic potential of the XPA-4G>A in unresected NSCLC treated with radiotherapy and chemoradiotherapy. The results require validation in an independent population.     

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.     

Polymorphisms of the NER pathway genes, <Emphasis Type="Italic">ERCC1</Emphasis> and <Emphasis Type="Italic">XPD</Emphasis> are associated with esophageal adenocarcinoma risk

Purpose  Functional variation in DNA repair capacity through single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer. Studies have focused on the nucleotide excision repair (NER) and base excision repair (BER) pathways. We investigated whether variant alleles in seven SNPs within these pathways increased the risk of esophageal adenocarcinoma. Methods  DNA was extracted from prospectively collected blood specimens. The samples were genotyped for SNPs in NER genes (XPD Lys751Gln, XPD Asp312Asn, ERCC1 8092C/A, and ERCC1 118C/T), and BER genes (XRCC1 Arg399Gln, APE1 Asp148Glu, and hOGG1 Ser326Cys). The presence of variant alleles was correlated with risk of esophageal adenocarcinoma both individually and jointly. Results  Variant alleles in NER SNPs XPD Lys751Gln (AOR = 1.50, 95% CI 1.1–2.0), ERCC1 8092 C/A (AOR = 1.44, 95% CI 1.1–1.9), and ERCC1 118C/T (AOR = 1.42, 95% CI 1.0–1.9) were individually associated with esophageal adenocarcinoma risk. An increasing number of variant alleles in NER SNPs showed a significant trend with esophageal adenocarcinoma risk (p = 0.007). Conclusions  The presence of variant alleles in NER genes increases risk of esophageal adenocarcinoma. There is evidence of an additive role for SNPs along a common DNA repair pathway. Future larger studies of esophageal adenocarcinoma etiology should evaluate entire biological pathways.     

Nucleotide excision repair pathway genes and oral premalignant lesions.

PURPOSE: Oral premalignant lesions (OPL) are associated with tobacco exposure and an increase in risk of oral cancer. Nucleotide excision repair (NER) is one of the major DNA repair pathways involved in the removal of tobacco carcinogen adducts. Polymorphisms in NER genes may cause variations in DNA repair capacity and increase susceptibility to both premalignant lesions and cancer. EXPERIMENTAL DESIGN: In this case-control study of 144 OPL patients and 288 controls, we genotyped 11 polymorphisms in 8 major NER genes, including XPA [A23G at 5' untranslated region (UTR)], XPD (Asp312Asn, Lys751Gln), XPC (Ala499Val, Lys939Gln), XPG (His1104Asp), XPF (Pro662Ser), ERCC6 (Met1097Val, Arg1230Pro) Rad23B (Ala249Val), and CCNH (Val270Ala). RESULTS: We found significant or borderline-significant associations between OPL risk and the polymorphisms XPA (A23G), XPD (Lys751Gln), XPC (Ala499Val), Rad23B (Ala249Val), and XPD (Asp312Asn), with adjusted odds ratios (ORs) of 1.97 [95% confidence interval (95% CI), 1.27-3.06], 1.60 (95% CI, 1.02-2.51), 0.63 (95% CI, 0.40-1.00), 0.67 (95% CI, 0.41-1.07), and 1.42 (95% CI, 0.90-2.23), respectively. When further stratified analyses were done, the decreased risk conferred by the XPC (Ala499Val) variant allele was more evident in older individuals (OR, 0.50; 95% CI, 0.24-1.03), in women (OR, 0.46; 95% CI, 0.21-1.01), in ever smokers (OR, 0.59; 95% CI, 0.33-1.05), and in never drinkers (OR, 0.42; 95% CI, 0.18-1.00). Finally, we found joint effects between these NER gene variants and smoking status. For example, when never smokers with the XPA 23A genotypes were used as the reference group, the ORs for never smokers with the XPA 23G genotype, smokers with the 23A genotype, and smokers with 23G genotypes were 2.19 (1.07-4.46), 2.64 (1.42-4.89), and 5.04 (2.62-9.69), respectively. Gene-gene and gene-smoking interaction for OPLs risk were also confirmed by multifactor dimensionality reduction (MDR) analysis in our study. MDR analysis revealed that a model containing ever smoking, XPA (A23G), XPC (Ala499Val), and XPD (Asp312Asn) was the best model to predict OPL risk with maximum average cross-validation consistency and minimum prediction error (P < 0.001). CONCLUSION: Our results suggest that polymorphisms in NER genes may contribute to genetic susceptibility to OPLs and may therefore contribute to the development of oral cancer.     

Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours

We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.     

APEX1 Asp148Glu Gene Polymorphism is a Risk Factor for Lung Cancer in Relation to Smoking in Japanese

DNA repair enzymes play an important role in the development of various kinds of cancer. We hereanalyzed associations of XPD Lys751Gln, APEX1 Asp148Glu, XRCC1 Arg399Gln, and XRCC3 Thr241Metgene polymorphisms in DNA repair pathways in relation to the risk of lung cancer using PCR-RFLP. The studyinvolved 104 lung cancer patients and 120 non-cancer controls divided into non-smokers and smokers. Wefound a statistically significant interaction between APEX1 Asp148Glu and the risk for lung cancer (adjustedOR 2.78, 95% CI 1.58-4.90, p=0.0004), of both adenocarcinoma (adjusted OR 2.24, 95%CI 1.18-4.25, p=0.014)and squamous cell carcinoma (adjusted OR 4.75, 95%CI 1.79-12.60, p=0.002) types. XRCC1 Arg399Gln showeda borderline significant association with adenocarcinoma (adjusted OR 1.89, 95%CI 1.00-3.57, p=0.051). Thecombined effect of smoking and presence of the APEX1 Asp148Glu demonstrated a significant association withrisk of lung cancer (adjusted OR 3.61, 95% CI 1.74-7.50, p = 0.001). The XPD Lys751Gln and XRCC3 Thr241Metgenotypes displayed no statistically significant risk. Our findings suggest that the APEX1 Asp148Glu is associatedwith increased risk for primary lung cancer in Japanese individuals partaking in smoking.     

Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

DNA repair enzymes repair DNA damaged by platinum agents and ionising radiation. Single nucleotide polymorphisms (SNPs) in DNA repair genes modulate the repair capacity and might affect response and prognosis following platinum-based chemoradiotherapy (CRT). We investigated associations between the functional SNPs in DNA repair genes and response and survival in muscle-invasive bladder cancer patients treated with CRT to determine the predictive value of the SNPs in patient selection for bladder conservation therapy. The study group comprised 78 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms in xeroderma pigmentosum complementation groups C (Lys939Gln, A/C), D (XPD; Lys751Gln, A/C), and G (Asp1104His, G/C), and X-ray repair cross-complementing groups 1 (XRCC1; Arg399Gln, G/A) and 3 (Thr241Met, T/C) genes were genotyped. Combined genotypes with at least one variant allele in XPD or XRCC1 were significantly associated with improved cancer-specific survival compared with remaining groups (P=0.009). In multivariate analysis, only the combined XPD and XRCC1 genotypes were independently associated with cancer-specific survival (P=0.04). The association was stronger in stage T3/T4 patients (P=0.0008). These results suggest that combined XPD and XRCC1 genotypes might be prognostic factors in muscle-invasive bladder cancer patients treated with CRT.     

Polymorphisms in DNA repair and metabolic genes in bladder cancer

We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.     

The Investigation of Polymorphisms in DNA Repair Genes (XRCC1, APE1 and XPD) in Women with Polycystic Ovary Syndrome

Background: PCOS was reported to arise from the interaction of genetic and environmental factors. Some studies reported that women with PCOS have DNA damage and chromosome breakage. Such studies bring to mind the genes that are involved in DNA repairing. At present, several DNA repair genes and, as products of these genes, certain polymorphisms that alter the activity of proteins are known in the literature. The aim of this dissertation is to study the genomic instability that have been reported in PCOS cases along with the relationship between XRCC1 Arg194Trp, XRCC1 Arg399Gln, APE1 Asp148Glu, and XPD Lys751Gln polymorphisms in order to contribute to the pathogenesis of PCOS. Methods: Polymorphisms in DNA repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of PCOS. Therefore, we conducted a study including 114 women with PCOS and 91 controls. These polymorphisms were determined by quantitative real time PCR and melting curve analysis using LightCycler. Results: Comparing the control groups at the end of the study, the results have not shown any statistically significant difference as far as XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XPD Lys751Gln polymorphisms are concerned. However, there were notable differences between the groups in terms of APE1 Asp148Glu polymorphism. Associated with this condition, it has been noted that both mutant allele (Glu) frequency (37.72 % in the study group; 19.23% in the control group, p=0.0001) and homozygous mutant genotype (Glu/Glu) frequency (%12.28 in the study group; %6.60 in the control group, p=0.015) have been higher in the study group.     

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.     

XRCC1 and XPD polymorphisms and esophageal adenocarcinoma risk

DNA damage is important in the pathogenesis of esophageal adenocarcinoma (EA). Polymorphic variants in DNA repair genes may be modifiers of the risk of EA through their role in altering human host response to gastroesophageal acid reflux, a well-described risk factor for EA. We studied the role of genetic polymorphisms of two key DNA repair genes, xeroderma pigmentosum group D (XPD) (Asp312Asn and Lys751Gln) in the nucleotide excision repair (NER) pathway and X-ray repair cross-complementing gene 1 (XRCC1) (Arg399Gln) in the base excision repair (BER) pathway, in the development of EA in 183 cases and 336 frequency-matched controls for age, gender and race. Genomic DNA was extracted from blood samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from logistic regression models, adjusted for body mass index at 18 years of age, smoking and alcohol exposure. The variant genotypes of XPD Lys751Gln polymorphism were associated with a higher risk of EA; the adjusted OR comparing Gln/Gln + Lys/Gln with Lys/Lys was 1.49 (95% CI: 1.02-2.14). Although no significant relationships were found for the XRCC1 Arg399Gln polymorphism alone, this polymorphism did modify the relationship between XPD Lys751Gln and EA risk; when both polymorphisms were evaluated together, adding the number of variant alleles of the two polymorphisms resulted in a significant trend (trend test, P = 0.008); compared with individuals with no variant alleles (n = 88), the adjusted ORs of developing EA are 1.49 (95% CI: 0.88-2.59), 1.69 (95% CI: 0.98-2.96) and 2.58 (95% CI: 1.31-5.06) for one (n = 195), two (n = 166) and three or four variant alleles (n = 70), respectively. No relationships were found for the XPD Asp312Asn polymorphism. We conclude that combined NER and BER pathways are important to the development of EA.