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)     

No association between XRCC1 and XRCC3 gene polymorphisms and breast cancer risk: Iowa Women's Health Study

BACKGROUND: Genetic variation in DNA repair may contribute to differences in the susceptibility of several cancers. We evaluated two polymorphisms in the base excision repair pathway (BER) (XRCC1; Arg194Trp and Arg399Gln) and one polymorphism in the double strand DNA repair pathway (XRCC3; Thr241Met) for their association with breast cancer risk. METHODS: The association was analyzed in a nested case control study of 460 breast cancer cases and 324 cancer-free controls within the Iowa Women's Health Cohort. DNA was obtained from blood samples or paraffin embedded tissues (PET) and all samples were genotyped by one of three genotyping platforms-PCR-RFLP, PCR-INVADER, or Sequenom. RESULTS: None of the three polymorphisms studied were significantly associated with breast cancer risk (XRCC1: Arg194Trp (OR=1.21, 95% CI: 0.78-1.88); Arg399Gln (OR=1.20, 95% CI: 0.80-1.79); XRCC3: Thr241Met (OR=1.04, 95% CI: 0.76-1.41). CONCLUSIONS: These results suggest that independently these polymorphisms of XRCC1 and XRCC3 genes do not contribute significantly to the genetic susceptibility of breast cancer.     

Hodgkin lymphoma risk: role of genetic polymorphisms and gene-gene interactions in DNA repair pathways

DNA repair variants may play a potentially important role in an individual's susceptibility to developing cancer. Numerous studies have reported the association between genetic single nucleotide polymorphisms (SNPs) in DNA repair genes and different types of hematologic cancers. However, to date, the effects of such SNPs on modulating Hodgkin lymphoma (HL) risk have not yet been investigated. We hypothesized that gene-gene interaction between candidate genes in direct reversal, nucleotide excision repair (NER), base excision repair (BER) and double strand break (DSB) pathways may contribute to susceptibility to HL. To test this hypothesis, we conducted a study on 200 HL cases and 220 controls to assess associations between HL risk and 21 functional SNPs in DNA repair genes. We evaluated potential gene-gene interactions and the association of multiple polymorphisms in a chromosome region using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction and classification and regression tree approaches. We observed that, in combination, allelic variants in the XPC Ala499Val, NBN Glu185Gln, XRCC3 Thr241Me, XRCC1 Arg194Trp, and XRCC1 399Gln polymorphisms modify the risk for developing HL. Moreover, the cumulative genetic risk score revealed a significant trend where the risk for developing HL increases as the number of adverse alleles in BER and DSB genes increase. These findings suggest that DNA repair variants in BER and DSB pathways may play an important role in the development of HL.     

Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis

Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Although cigarette smoking is the main cause of lung cancer, not all smokers develop lung cancer, and a fraction of lifelong non-smokers will die from lung cancer. Genetic host factors have recently been implicated to account for some of the observed differences in lung cancer susceptibility. Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, may result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent genetic association studies on lung cancer risk have focused on identifying effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide base repair (BER) pathway, focusing on 8-oxoguanine DNA glycosylase 1, X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1. The 399Gln/Gln genotype of the XRCC1 Arg399Gln polymorphism was associated with an increased risk of lung cancer among Asians (OR=1.34, 95% CI=1.16-1.54) but not among Caucasians. Little evidence of associations has been found between other BER genes and lung cancer risk. Considering the data available, it can be conjectured that if there is any risk association between single SNP and lung cancer, this risk increase/decrease will probably be minimal. Advances in identification of new polymorphisms and in high-throughput genotyping techniques will facilitate analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples of cases and controls.     

Polymorphisms of DNA repair genes are risk factors for prostate cancer

DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity. We hypothesised that DNA repair gene polymorphisms may be risk factors for prostate cancer (PC). To test this hypothesis, DNA samples from 165 cases of prostate cancer and healthy controls were analyzed by PCR-RFLP to determine the genotypic frequency of three DNA repair genes (XRCC1, XPC and XRCC7). We found that the frequency of 939Gln variant at XPC Lys939Gln was significantly lower in PC cases (OR=0.39, P=0.016). Haplotype analysis of XRCC1 Arg194Trp (C/T) and Arg399Gln (G/A) revealed that the frequency of the T-A haplotype was significantly higher in PC patients. This is the first report on the studies of XPC and XRCC1 Arg194Trp polymorphisms in PC, and our present data suggest that XPC Lys939Gln and the T-A haplotype of XRCC1 Arg194Trp and Arg399Gln may be risk factors for PC in Japanese.     

Polymorphisms of DNA repair genes and risk of non-small cell lung cancer

Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean.     

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.     

Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses' Health Study

Dietary folate and alcohol consumption as well as polymorphic variants in one-carbon metabolism genes may modulate risk of colorectal adenoma through aberrant DNA methylation and altered nucleotide synthesis and repair. We assessed the association of 24 non-synonymous single nucleotide polymorphisms (nsSNPs) in 13 genes in the one-carbon metabolism pathway and risk of colorectal adenoma in 556 incident cases and 557 controls nested in the Nurses' Health Study. Most of the SNPs were not associated with risk of colorectal adenoma. We did, however, observe a modest increased risk among carriers of the transcobalamin (TCN) II 259 Pro/Arg + Arg/Arg variant (odds ratio 1.48, 95% confidence interval 1.09-2.02) for colorectal adenoma. The TCN II Pro259Arg polymorphism may affect TCN binding and transport of vitamin B(12) and thus warrants further investigation of its biological function. In addition, the methionine synthase reductase (MTRR) Arg415Cys and MTRR Ser284Thr variant carriers, also in the vitamin B(12) pathway, have suggestive associations with advanced colorectal adenoma (defined as being larger than 1 cm, villous, tubular-villous or carcinoma in situ histology). We observed significant evidence for departure from multiplicative interaction for the betaine-homocysteine methyltransferase (BHMT) Arg239Gln with dietary methyl status (based on intake of dietary folate, methionine and alcohol intake) in relation to colorectal adenoma; no such interaction was observed for the other 23 SNPs. Further investigation is required to validate the association of the polymorphisms in the one-carbon metabolic genes and risk of colorectal adenoma.     

Large-scale evaluation of genetic variants in candidate genes for colorectal cancer risk in the Nurses' Health Study and the Health Professionals' Follow-up Study

Advances in genomics offer new strategies for assessing the association of common genetic variations at multiple loci and risk of many diseases, including colorectal cancer. Low-penetrance alleles of genes in many biological pathways, such as DNA repair, metabolism, inflammation, cell cycle, apoptosis, and Wnt signaling, may influence the risk of nonfamilial colorectal cancer. To identify susceptibility genes for colorectal cancer, we designed a large-scale case-control association study nested within the Nurses' Health Study (190 cases and 190 controls) and the Health Professionals' Follow-up Study (168 cases and 168 controls). We used a custom GoldenGate (Illumina) oligonucleotide pool assay including 1,536 single nucleotide polymorphisms (SNP) selected in candidate genes from cancer-related pathways, which have been sequenced and genotyped in the SNP500Cancer project; 1,412 of the 1,536 (92%) of the SNPs were genotyped successfully within 388 genes. SNPs in high linkage disequilibrium (r(2) >/= 0.90) with another assayed SNP were excluded from further analyses. As expected by chance (and not significant compared with a corrected Bonferroni P = 0.00004), in the additive model, 11 of 1,253 (0.9%) SNPs had a P(trend) < 0.01 and 38 of 1,253 (3.0%) SNPs had a P(trend) >/= 0.01 and P(trend) < 0.05. Of note, the MGMT Lys(178)Arg (rs2308237) SNP, in linkage disequilibrium with the previously reported MGMT Ile(143)Val SNP, had an inverse association with colorectal cancer risk (MGMT Lys(178)Arg: odds ratio, 0.52; 95% confidence interval, 0.35-0.78; unadjusted P(trend) = 0.0003 for the additive model; gene-based test global P = 0.00003). The SNP500Cancer database and the Illumina GoldenGate Assay allowed us to test a larger number of SNPs than previously possible. We identified several SNPs worthy of investigation in larger studies.     

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.     

Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk.

An epidemiologic study was conducted to determine whether polymorphisms in DNA repair genes modify the association between breast cancer risk and exposure to ionizing radiation. Self-reported exposure to ionizing radiation from medical sources was evaluated as part of a population-based, case-control study of breast cancer in African-American (894 cases and 788 controls) and White (1,417 cases and 1,234 controls) women. Genotyping was conducted for polymorphisms in four genes involved in repair of radiation-induced DNA damage, the double-strand break repair pathway: X-ray cross-complementing group 3 (XRCC3) codon 241 Thr/Met, Nijmegen breakage syndrome 1 (NBS1) codon 185 Glu/Gln, X-ray cross-complementing group 2 (XRCC2) codon 188 Arg/His, and breast cancer susceptibility gene 2 (BRCH2) codon 372 Asn/His. Allele and genotype frequencies were not significantly different in cases compared with controls for all four genetic polymorphisms, and odds ratios for breast cancer were close to the null. Combining women with two, three, and four variant genotypes, a positive association was observed between breast cancer and number of lifetime mammograms (P(trend) < 0.0001). No association was observed among women with zero or one variant genotype (P = 0.86). Odds ratios for radiation treatments to the chest and number of lifetime chest X-rays were slightly elevated but not statistically significant among women with two to four variant genotypes. The study has several limitations, including inability to distinguish between diagnostic and screening mammograms or reliably classify prediagnostic mammograms and chest X-rays in cases. Prospective studies are needed to address whether common polymorphisms in DNA repair genes modify the effects of low-dose radiation exposure from medical sources.     

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.     

Complex association between ERCC2 gene polymorphisms,gender, smoking and the susceptibility to bladder cancer: a meta-analysis

Genetic polymorphisms in DNA repair genes may be involved in increasing the risk of bladder cancer. Association studies on the excision repair cross-complementation group 2 (ERCC2) gene polymorphisms and bladder cancer risk have reported conflicting results. The aim of this meta-analysis of eligible cancer case-control studies is to investigate the role of ERCC2 SNPs (Arg156Arg, Asp312Asn, and Lys751Gln), gender and smoking in determining susceptibility to bladder cancer. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar databases to indentify eligible studies published before December 1, 2013. We performed a meta-analysis of 23 case-control studies with a total of 7,062 bladder cancer patients and 8,832 controls. The overall analysis suggested that ERCC2 Arg156Arg, Asp312Asn, and Lys751Gln are associated with increased bladder cancer risk. For ERCC2 Arg156Arg, the mutant allele was associated with a 1.36-fold (95 % CI?=?1.15–1.61) increased risk of bladder cancer. For ERCC2 Asp312Asn, individuals with the Asn allele were associated with a 1.29-fold (95 % CI?=?1.13–1.48) increased risk of bladder cancer. For ERCC2 Lys751Gln, individuals who carried the variant heterozygote Lys/Gln or homozygote Gln/Gln had a significantly increased bladder cancer risk, compared with the wild genotype Lys/Lys (OR?=?1.10, 95 % CI?=?1.03–1.18). Furthermore, gender and smoking may modify the association between these SNPs and bladder cancer risk. This study provides the strongest evidence to date for the role of common variants of the ERCC2 gene in bladder carcinogenesis. Further studies comprehensively characterizing other DNA repair pathways and accounting for exposure to relevant environmental factors should offer further insight into the role of DNA repair in bladder cancer.     

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.     

DNA Repair Gene Polymorphisms at XRCC1, XRCC3, XPD,and OGG1 Loci in the Hyderabad Population of India

Background: DNA repair is one of the crucial defense mechanism against mutagenic exposure. Inherited SNPs of DNA repair genes may contribute to variation in DNA repair capacity and susceptibility to cancer. Due to thepresence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. India harbors enormous genetic and cultural diversity. Materials and Methods: In the present study we aimed to determine the genotypes and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 186 healthy individuals residing in the Hyderabad region of India and to compare them with HapMap and otherpopulations. Results and Conclusions: The genotype and allele frequency distribution at the four DNA repairgene loci among Hyderabad population of India revealed a characteristic pattern. Comparison of these genepolymorphisms with other populations revealed a distinctiveness of Hyderabad population from the Deccanregion of India. To the best of our knowledge, this is the first report of such DNA repair gene polymorphisms inthe Deccan Indian population.     

Genetic polymorphisms of XRCC1 and risk of gastric cancer

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

Selected genetic polymorphisms in MGMT, XRCC1, XPD, and XRCC3 and risk of head and neck cancer: a pooled analysis.

Tobacco and alcohol consumption are the major risk factors for head and neck cancer, likely due to DNA-damaging processes. Genetic variations in DNA repair genes may affect an individual's susceptibility to head and neck cancer. Pooling data and DNA specimens from three case-control studies in western Washington State, North Carolina, and Puerto Rico, totaling 555 cases (430 whites) and 792 controls (695 whites), we studied the risk of head and neck cancer in relation to common nonsynonymous single-nucleotide polymorphisms in four DNA repair genes: MGMT (Leu84Phe and Ile143Val), XRCC1 (Arg399Gln), XPD (Lys751Gln), and XRCC3 (Thr241Met). All single-nucleotide polymorphisms were assayed in a single laboratory. Among whites, carriage of the MGMT Phe84 [odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.98] or Val143 (OR, 0.66; 95% CI, 0.47-0.92) allele was associated with a decreased risk of head and neck cancer; the haplotype distribution for MGMT differed significantly between cases and controls (covariate-adjusted global permutation test, P = 0.012). The XRCC1 GlnGln399 genotype was also associated with decreased risk among whites (OR, 0.56; 95% CI, 0.32-0.94), whereas XPD751 and XRCC3241 were not associated with risk. Alcohol-related risks tended to vary with DNA repair genotypes, especially for MGMT variants, whereas no effect modification was noted with tobacco use. Consistent findings from three case-control studies suggest that selected DNA repair enzymes may play a role in head and neck carcinogenesis.     

Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk.

The variability in DNA repair capacity of the general population may depend in part upon common variants in DNA repair genes. X-ray repair cross complementing group 1 (XRCC1) is an important DNA base excision repair gene and exhibits polymorphic variation. Using the Long Island Breast Cancer Study Project, a population-based case-control study, we evaluated the hypothesis that two common single nucleotide polymorphisms of XRCC1 (codon 194 Arg-->Trp and 399 Arg-->Gln) influence breast cancer susceptibility and interact with polycyclic aromatic hydrocarbon (PAH)-DNA adducts, cigarette smoking, and intake of fruits and vegetables and antioxidants. The available sample for genotyping included 1,067 cases and 1,110 controls. Genotyping was done by a high-throughput single-nucleotide extension assay with fluorescence polarization detection of the incorporated nucleotide. We observed no significant increases in risk among all subjects who were carriers of XRCC1 194Trp or 399Gln alleles. Among never smokers, we observed an increased risk of breast cancer in 399Gln carriers [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7). Further analysis indicated a suggestive weak additive interaction between the 399Gln allele and detectable PAH-DNA adducts (OR for exposure with mutant genotype, 1.9; 95% CI, 1.2-3.1). The estimated age-adjusted interaction contrast ratio (ICR) and 95% CI (ICR, 0.38; 95% CI, -0.32 to 1.10) indicated that the departure from additivity was not statistically significant, but that there was some suggestion of a relative excess risk due to the interaction. In subjects with at least one copy of XRCC1 194Trp allele, there was a moderate interaction with high intake of fruits and vegetables (>/=35 half-cup servings per week of any fruits, fruit juices, and vegetables, OR, 0.58; 95% CI, 0.38-0.89; ICR, -0.49; 95% CI, -0.03 to -0.95), and dietary plus supplement antioxidant intake with 33% to 42% decreases in breast cancer risk compared with those with the Arg194Arg genotype and low-intake individuals. These results do not show that the two genetic polymorphisms of XRCC1 independently influence breast cancer risk. However, there is evidence for interactions between the two XRCC1 single nucleotide polymorphisms and PAH-DNA adducts or fruit and vegetable and antioxidant intake on breast cancer risk. Further understanding of the biological function of XRCC1 variants and their interactions with PAH-DNA adducts, antioxidants, and other genes in the pathway are needed.     

Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations

Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ～ 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.     

Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma

The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for ESCC. We first screened eight BER genes for new and potential functional polymorphisms by resequencing 27 DNA samples. We then identified and genotyped for important tagging single nucleotide polymorphisms (SNPs) in a case-control study of 419 patients with newly diagnosed esophageal cancer and 480 healthy controls by frequency matching on age and sex. The association between genotypes and ESCC risk was estimated by unconditional multivariate logistic regression analysis, and stepwise regression procedure was used for constructing the final logistic regression model. We identified 129 SNPs in the eight BER genes, including 18 SNPs that cause amino acid changes. In the final model, 4 SNPs, including 2 in the coding regions (ADPRT Val762Ala and MBD4 Glu346Lys) and others in noncoding regions (LIG3 A3704G and XRCC1 T-77C), remained as significant predictors for the risk of ESCC. The adjusted odd ratios were 1.25 [95% confidence interval (CI) 1.02-1.53] for the ADPRT 762Ala allele, 1.25 (95% CI 1.02-1.53) for the MBD4 346 Lys allele, 0.78 (95% CI 0.63-0.97) for the LIG3 3704G allele, and 1.38 (95% CI 1.01-1.89) for the XRCC1-77C allele. In addition, we observed a significant gene-gene interaction between XRCC1 Gln399Arg and ADPRT Val762Ala. The results suggest that the polymorphisms in five BER genes may be associated with the susceptibility to ESCC in a Chinese population.