XRCC1 polymorphisms and head and neck cancer

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

Polymorphisms of the XRCC1 DNA repair gene in head and neck cancer

Inherited polymorphisms in the genes controlling the cell cycle or functioning in the DNA repair mechanisms may impair their function and contribute to genetic susceptibility. Abnormalities in the DNA repair have been reported in head and neck cancer. The XRCC1 gene functions in singlestrand break and base excision repair processes. In this study, two polymorphisms of the XRCC1 gene, Arg194Trp and Arg399Gln were investigated in 95 patients with head and neck carcinoma. The polymorphic regions were amplified by PCR followed by digestion with methylation-specific restriction enzymes, and analyzed electrophoretically. Genotype and allele frequencies were calculated, and association with cancer risk or clinical parameters was investigated. No association was observed between the genotypes and head and neck cancer for either polymorphism. Distribution of the alleles did not significantly differ between the patients and the control group. A significant association was only found for the Trp194 allele among the smoking individuals. Our data indicate that the Arg194Trp and Arg399Gln polymorphisms do not confer a significant risk for head and neck carcinogenesis.     

XRCC1 polymorphisms and risk of nasopharyngeal carcinoma: a meta-analysis

Objective: Previous studies on the association between X-ray repair cross-complementing protein 1 (XRCC1) polymorphisms and nasopharyngeal carcinoma (NPC) risk showed inconsistent results. The aim of this study was to evaluate the effects of XRCC1 variants on NPC risk. Methods: A meta-analysis was performed with all eligible studies covering a total of 1,341 cases and 1,425 controls for the Arg194Trp polymorphism, 1,260 cases and 1,207 controls for the Arg280His polymorphism, and 1,644 cases and 1,678 controls for the Arg399Gln polymorphism. Results: No associations was found between Arg194Trp and Arg280His polymorphisms with NPC risk under all contrast models (co-dominant, dominant, and recessive models). However a deleterious effect of the 399Gln genotype was observed under the co-dominant model (Gln/Gln versus Arg/Arg, OR = 1.30, 95% CI : 1.01-1.69, P = 0.04). Under the recessive model (Gln/Gln versus Arg/Arg+Arg/Gln), the P value was marginally significant (OR = 1.28, 95% CI : 1.00-1.65, P = 0.05). However, the effect of the 399Gln genotype on NPC became non-significant after excluding one study from the meta-analysis because of departure from Hardy-Weinberg equilibrium. Conclusions: No associations was found between Arg194Trp and Arg280His polymorphisms with NPC risk, whereas the Arg399Gln genotype was associated with increased risk.     

XRCC1基因多态性与贲门癌的发病风险

目的通过病例-对照研究,探讨X-射线交错互补修复基因1(X-ray repair cross-complementing gene 1, XRCC1)基因多态性与贲门腺癌(gastric cardiac adenocarcinoma, GCA)发病风险的关系。方法采用聚合酶链反应 限制性片段长度多态性技术检测455例GCA 患者和650例对照人群XRCC1 Arg194Trp、Arg280His及Arg399Gln 3个多态性位点基因型和等位基因频率分布情况。结果XRCC1 Arg194Trp及Arg399Gln多态位点的基因型及等位基因型频率的分布在患者组和对照组之间无明显的差异（P>0.05）。但以吸烟和家族史状况分层分析发现,吸烟组中GCA患者280位点的His等位基因频率为11.5％,明显高于对照组8.2％,GCA患者组和健康对照组中Arg/Arg、Arg/His、His/His三种基因型频率分别是77.9％、21.2％、0.9％和84.9％、13.7％、1.4％,两组相比差异具有统计学意义（χ²=4.107,P=0.043）。与Arg/Arg基因型相比,携带His等位基因（Arg/His+His/His）可明显增高吸烟人群GCA的发病风险（OR=1.572, 95％CI=1.00~2.51）。结论本研究结果提示XRCC1基因Arg194Trp、Arg399Gln多态位点可能与GCA的发病风险无关,但Arg280His多态的His等位基因型可能增加吸烟人群GCA的发病风险。     

Variant Alleles in XRCC1 Arg194Trp and Arg399Gln Polymorphisms Increase Risk of Gastrointestinal Cancer in Sabah,North Borneo

Background: The XRCC1 protein facilitates various DNA repair pathways; single-nucleotide polymorphisms (SNPs) in this gene are associated with a risk of gastrointestinal cancer (GIC) with inconsistent results, but no data have been previously reported for the Sabah, North Borneo, population. We accordingly investigated the XRCC1 Arg194Trp and Arg399Gln SNPs in terms of GIC risk in Sabah. Materials and Methods: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction- restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing. Results: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects 50 years and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC. Conclusions: Our findings suggest that inheritance of variant alleles in XRCC1 Arg194Trp and Arg399Gln SNPs may act as biomarkers for the early detection of GIC, especially for gastric and colorectal cancers in the Sabah population.     

Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer.

DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents, such as those found in tobacco smoke. Reduced DNA repair capacity, therefore, can increase the susceptibility to smoking-related cancers. Recently, three coding polymorphisms in X-ray cross-complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. We investigated the relationship between the codon 399 polymorphism in XRCC1 gene and lung cancer risk in male smokers. The study population consisted of 192 lung cancer patients and 135 healthy controls. The distribution of XRCC1 genotypes was not significantly different between cases and controls. When the cases were categorized by histological type, however, the presence of at least one Gln allele was associated with a significant increased risk for squamous cell carcinoma [crude odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.06-2.93 and adjusted OR = 1.66, 95% CI = 0.99-2.79]. The risk for the disease increased as the number of Gln alleles increased (Arg/Gln genotype: adjusted OR = 1.45, 95% CI = 0.84-2.5; Gln/Gln genotype: adjusted OR = 3.26, 95% CI = 1.17-9.15). When the subjects dichotomized by cigarette consumption into two pack-year groups (< or =40 pack-years, >40 pack-years), the Gln allele was associated with an increased risk for squamous cell carcinoma only in the group of individuals having < or =40 pack-years of smoking (Arg/Gln genotype: adjusted OR = 1.48, 95% CI = 0.78-2.8; Gln/Gln genotype: adjusted OR = 5.75, 95% CI = 1.46-22.69). These results suggest that XRCC1 codon 399 polymorphism may be an important genetic determinant of squamous cell carcinoma of the lung in persons with lower degrees of cigarette use.     

Genetic variation in XRCC1, sun exposure, and risk of skin cancer

The XRCC1 gene is involved in the base excision repair pathway. We assessed the associations of polymorphisms and haplotypes in XRCC1 with skin cancer risk in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC) and 300 basal cell carcinoma (BCC), and 873 controls). We genotyped four haplotype-tagging single-nucleotide polymorphisms (Arg194Trp, C26602T, Arg399Gln, and Gln632Gln). There was no significant difference in frequency distribution between cases and controls for any of the five inferred common haplotypes. We observed that the 399Gln allele was inversely associated with SCC risk. This inverse association was only seen among those who had five or more lifetime sunburns, those with a family history of skin cancer, and those in the highest tertile of cumulative sun exposure in a bathing suit, but not among those with low risk defined by these risk factors. We also observed a significant association of the carriage of 194Trp allele with increased SCC risk, which was modified by family history of skin cancer. These two polymorphisms were not associated with BCC or melanoma risk. Our data suggest that the Arg194Trp and Arg399Gln polymorphisms may be differently associated with skin cancer risk according to exposure dose and skin cancer type.     

XRCC1 polymorphisms, cooking oil fume and lung cancer in Chinese women nonsmokers

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.     

Single nucleotide polymorphisms of DNA repair genes XRCC1 and XPD and its molecular mapping in Indian oral cancer

Tobacco users with diminished ability to repair somatic mutations may be more susceptible to tobacco attributable cancers. The distribution of single nucleotide polymorphisms (SNPs) in DNA repair genes XRCC1 and XPD in 110 oral carcinoma cases, 84 leukoplakia and 110 controls belonging to the Travancore South Indian population were examined. SNPs investigated included Arg194Trp, Arg280His, and Arg399Gln of the XRCC1 gene and Lys751Gln of the XPD gene. In addition, one of the variants positions, A399G, was mapped onto the BRCT I domain model built by comparative modeling (threading). Presence of the polymorphic variant of XRCC1 codon 194 and 399 and XPD was associated with increased risk of oral cancer compared to the wild genotype. Smokers and betel quid chewers with the variant allele of XRCC1 399 codon and XPD also exhibited increased risk of oral cancer. The A399G variant position mapped onto the surface of the BRCT I domain provides a possible rationale for altered XRCC1 function. These results suggest that polymorphisms in functionally important repair genes, specifically, those that map onto the protein surface may alter protein function without significantly affecting its structure.     

Polymorphisms in the DNA repair gene XRCC1 associated with basal cell carcinoma and squamous cell carcinoma of the skin in a Korean population

DNA in most cells is regularly damaged by endogenous and exogenous mutagens. Unrepaired damage can result in apoptosis or may lead to unregulated cell growth and cancer. Inheritance of genetic variants at one or more loci results in reduced DNA repair capacity. This hospital-based case-control study examined whether polymorphisms in the DNA repair gene X-ray repair cross-complementing groups 1 ( XRCC1 ) (Arg194Trp[C > T], Arg280His[G > A] and Arg399Gln[G > A]) play a role in susceptibility to skin cancer. We genotyped these polymorphisms for 212 histopathologically confirmed skin cancer cases ( n  = 114 basal cell carcinoma, n  = 98 squamous cell carcinoma) and 207 age- and sex-matched healthy control cases in Korea. We found that individuals with the Arg/Gln and Arg/Gln + Gln/Gln genotypes at XRCC1 Arg399Gln(G > A) had an approximately 2-fold increased risk of basal cell carcinoma compared to individuals with the Arg/Arg genotype (adjusted odds ratio [AOR] = 2.812, 95% confidence interval [CI] 1.32–5.98, and AOR = 2.324, 95% CI 1.11–4.86). However, we observed that the 194Trp allele of the Arg194Trp(C > T) polymorphism was inversely associated with squamous cell carcinoma risk (Trp/Trp, AOR = 0.06, 95% CI 0.006–0.63). Our data suggest that the Arg194Trp and Arg399Gln polymorphisms may be differentially associated with skin cancer risk. ( Cancer Sci 2007; 98: 716–720)     

Genetic polymorphisms in DNA base-excision repair genes ADPRT, XRCC1, and APE1 and the risk of squamous cell carcinoma of the head and neck

BACKGROUND: Tobacco smoke contains numerous carcinogens that cause DNA damage, including oxidative lesions that are removed effectively by the base-excision repair (BER) pathway, in which adenosine diphosphate ribosyl transferase (ADPRT), x-ray repair cross-complementing 1 (XRCC1), and apurinic/apyimidinic endonuclease (APE1) play key roles. Genetic variations in the genes encoding for these DNA repair enzymes may alter their functions. Although there have been several studies that generated mixed results on the association between XRCC1 variants and the risk of squamous cell carcinoma of the head and neck (SCCHN), no reported studies have investigated the association between ADPRT and APE1 variants and SCCHN risk. METHODS: In a hospital-based, case-control study of 830 non-Hispanic white patients with SCCHN and 854 cancer-free, matched control participants, the authors genotyped the ADPRT alanine 762 valine (Ala762Val) single-nucleotide polymorphism (SNP), the XRCC1 arginine 399 glutamine (Arg399Gln) SNP, and the APE aspartic acid 148 glutamic acid (Asp148Glu) SNP and assessed their associations with the risk of SCCHN in multivariate logistic regression models. RESULTS: The findings indicated that a significantly decreased risk of SCCHN was associated with the ADPRT 762Ala/Ala genotype (adjusted odds ratio [OR], 0.51; 95% confidence interval [95% CI], 0.27-0.97) and the combined ADPRT 762Ala/Val and Ala/Ala genotypes (OR, 0.79; 95% CI; 0.63-1.00) compared with the ADPRT 762Val/Val genotype, but no altered risk was associated with the XRCC1 Arg399Gln or APE Asp148Glu polymorphisms, and no evidence of interactions was observed between the 3 selected SNPs and age, sex, smoking status, drinking status, or tumor site. CONCLUSIONS: The ADPRT Ala762Val polymorphism may play a role in the etiology of SCCHN or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes will be needed to verify these findings.     

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.     

XRCC1 Arg399Gln gene polymorphism and breast cancer risk: a meta-analysis based on case-control studies

Background: The Arg399Gln polymorphism in the XRCC1 DNA repair gene is likely to be involved with the development of breast cancer (BC). However, there have been inconsistent reports of association. The objective of this study was to systematically evaluate the published papers. Methods: We performed a meta-analysis of 44 published case-control studies fitting our eligibility criteria. These studies involved XRCC1 Arg399Gln polymorphisms in 20,841 BC cases and 22,688 controls in dominant (GlnGln+ArgGln vs. ArgArg), recessive (GlnGln vs. ArgGln+ArgArg), and co-dominant (GlnGln vs. ArgArg) inheritance models. Analyses of Asian, African and Caucasian ethnic subgroups was also conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Results: Our overall analyses indicated Arg399Gln to be associated with a trend of increased BC risk when using recessive (OR=1.15, 95%CI: 1.05–1.27), and co-dominant models (OR=1.15, 95%CI: 1.04-1.27) to analyze the data. In ethnic subgroups, Arg399Gln significantly increased BC risk in Asians (OR=1.54, 95%CI: 1.18–2.01) when using recessive model analysis, in Africans (OR=1.30, 95%CI: 1.07–1.60) when using dominant model analysis, and in Asians (OR=1.50, 95%CI: 1.15–1.97) and Africans (OR=1.80, 95%CI: 1.08-3.02) when using the co-dominant model analysis. Conclusions: From our meta-analysis of data from 44 publications, we conclude that XRCC1 Arg399Gln allele is a risk factor for the development breast cancer, especially among Asian and African populations.     

The association of XRCC1 gene single nucleotide polymorphisms with response to neoadjuvant chemotherapy in locally advanced cervical carcinoma

Background

Platinum-based neoadjuvant chemotherapy (NAC) is new therapeutic strategy for locally advanced cervical carcinoma, but the variables used to predict NAC response are still infrequently reported. The aim of our study was to investigate the association between XRCC1 gene single nucleotide polymorphisms (SNPs) and NAC response.

Methods

Seventy patients with locally advanced cervical carcinoma who underwent NAC were collected. SNPs of XRCC1 (at codon 194 and 399) and XRCC1 protein expression were detected. The association of XRCC1 gene SNPs and protein expression with NAC response were analyzed.

Results

Response to NAC was not statistically significant in three genotypes, Arg/Arg, Arg/Trp, Trp/Trp of XRCC1 at codon 194(X² = 1.243, P = 0.07), while responses were significantly different in genotypes Arg/Arg, Arg/Gln, Gln/Gln of XRCC1 at codon 399 (X² = 2.283, P = 0.020). The risk of failure to chemotherapy in the patients with a Gln allele(Arg/Gln+Gln/Gln) was significantly greater than that with Arg/Arg(OR = 3.254, 95%CI 1.708 ~ 14.951). The expression level of XRCC1 protein was significantly associated with response to NAC. Moreover, the genotype with the Gln allele(Arg/Gln+Gln/Gln) at codon 399, but not codon at 194, presented a significantly higher level of XRCC1 protein expression than that with Arg/Arg genotype (F = 2.699, p = 0.009).

Conclusion

SNP of XRCC1 gene at codon 399 influences the response of cervical carcinoma to platinum-based NAC. This is probably due to changes in expression of XRCC1 protein, affecting response to chemotherapy.     

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 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.     

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.     

The XRCC1 399Gln polymorphism and the frequency of p53 mutations in Taiwanese oral squamous cell carcinomas.

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.     

Genetic polymorphisms of XRCC1 and risk of the esophageal cancer

A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical-associated carcinogenesis. We hypothesized that the polymorphic XRCC1 genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCC1 genetic polymorphisms on codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (+/-3 years), gender and ethnicity. The distribution of the 3 genotypes were not significantly different among patients and controls. However, among alcohol drinkers, the XRCC1399 Arg/Arg genotype was more frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCC1399 Arg/Arg was 2.78 (95% CI =1.15-6.67) as compared with the XRCC1(399) Arg/Gln and XRCC1(399) Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCC1 genes might modify the risk of alcohol-associated esophageal cancers.     

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

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