Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p=0.001) for the Asp/Glu genotype and 2.39 (p=0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR=0.32, p=0.024; OR=0.25, p=0.028; OR=0.51, p=0.033, respectively). No associations with lung cancer risk were found for the XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.     

DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome

DNA repair plays a pivotal role in maintaining genomic integrity with over 130 genes involved in various repair pathways that include base excision repair, nucleotide excision repair, double strand break repair and DNA mismatch repair. Polymorphisms within genes that are involved in these processes have been widely reported to be associated with cancer susceptibility in an extensive range of malignancies that include colorectal cancer (CRC). Lynch syndrome is caused by inherited germline mutations in DNA mismatch repair genes, predominantly in MLH1 and MSH2, that predispose to a variety of epithelial malignancies, most notably CRC. Despite being a relatively well understood hereditary cancer syndrome there remain several questions in relation to genetic influences on disease expression. Since Lynch syndrome is associated with a breakdown in DNA mismatch repair variation in other DNA repair genes may influence disease expression. In this report we have genotyped 424 Australian and Polish Lynch syndrome participants for eight common DNA repair gene polymorphisms to assess any association with the age of CRC onset. The DNA repair gene SNPs included in the study were: BRCA2 (rs11571653), MSH3 (rs26279), Lig4 (rs1805386), OGG1 (rs1052133), XRCC1 (rs25487), XRCC2 (rs3218536 and rs1799793) and XRCC3 (rs861539). Cox multi-variant regression modelling failed to provide any convincing evidence of an effect in any of the polymorphisms analysed. The data suggest that polymorphisms in DNA repair genes do not contribute to cancer risk in a population of CRC patients who are at increased risk of disease as a result in a deficiency of DNA mismatch repair.     

The association of polymorphisms in DNA base excision repair genes <Emphasis Type="Italic">XRCC1</Emphasis>, <Emphasis Type="Italic">OGG1</Emphasis> and <Emphasis Type="Italic">MUTYH</Emphasis> with the risk of childhood acute lymphoblastic leukemia

The aim of this study was to evaluate the association of polymorphisms in genes encoding three key proteins of DNA base excision repair (BER): the OGG1 Ser326Cys, the MUTYH Tyr165Cys and the XRCC1 Arg399Gln with the risk of childhood acute lymphoblastic leukemia (ALL). Our study included 97 children patients with ALL (mean age 5.4 ± 2.5) and 131 healthy children (mean age 6.2 ± 2.8) used as controls. Genetic polymorphisms in BER pathway genes were examined using PCR and restriction fragment length polymorphism (RFLP). We have demonstrated that the OGG1 Cys/Cys genotype increases the risk of ALL (OR 5.36) whereas the Ser/Ser genotype variant strongly reduces the risk of this cancer among Polish children (OR 0.45). Although we did not observe the differences in single nucleotide polymorphisms (SNPs) in MUTYH and XRCC1 genes between control group and children with ALL, we have shown that the combined genotypes of examined genes can modulate the risk of childhood ALL in Polish population. We found that the combined genotype Arg/Gln–Cys/Cys of XRCC1/OGG1 (OR 3.83) as well as the Cys/Cys–Tyr/Tyr of OGG1/MUTYH (OR 6.75) increases the risk of ALL. In contrast, the combined genotype Arg/Arg–Ser/Ser of XRCC1/OGG1 (OR 0.40) as well as the Ser/Ser–Tyr/Tyr of OGG1/MUTYH (OR 0.43) played a protective role against this malignant disease. In conclusion, we suggest that polymorphisms of BER genes may be used as an important predictive factor for acute lymphoblastic leukemia in children.     

Impact of single nucleotide polymorphisms in the OGG1 and XRCC1 genes on modulation of DNA damage in pesticide-exposed agricultural workers in Punjab,North-West India

Abstract

Pesticide-induced DNA damage is primarily repaired by base excision repair (BER) pathway. However, polymorphism in DNA repair genes may modulate individual’s DNA repair capacity (DRC) leading to increased genotoxicity and adverse health effects. Our first study in North-West Indian population aimed to evaluate the impact of OGG1 rs1052133 (Ser326Cys; C1245G), XRCC1 rs1799782 (Arg194Trp; C26304T) and XRCC1 rs25487 (Arg399Gln; G28152A) polymorphisms on the modulation of pesticide-induced DNA damage in a total of 450 subjects (225 pesticide-exposed agricultural workers and 225 age- and sex-matched controls). DNA damage was estimated by alkaline comet assay using silver-staining method. Genotyping was carried out by PCR-RFLP using site-specific restriction enzymes. Mann-Whitney U-test revealed elevation in DNA damage parameters (p?<?0.01) in pesticide-exposed agricultural workers than controls. Chi-square test showed significant (p?<?0.05) differences in the XRCC1 Arg194Trp (C26304T) and Arg399Gln (G28152A) genotypes among two groups. Multivariate logistic-regression analysis revealed that heterozygous genotypes of OGG1 rs1052133 (326Ser/Cys; 1245CA), XRCC1 rs1799782 (194Arg/Trp; 26304CT) and XRCC1 rs25487 (399Arg/Gln; 2815GA) were positively associated (p?<?0.05) with elevated DNA damage parameters in pesticide-exposed agricultural workers. Our results strongly indicate significant positive association of variant OGG1 and XRCC1 genotypes with reduced DRC and higher pesticide-induced DNA damage in North-West Indian agricultural workers.     

Analysis of the polymorphisms XRCC1Arg194Trp and XRCC1Arg399Gln in gliomas

XRCC genes (X-ray cross-complementing group) were discovered mainly for their roles in protecting mammalian cells against damage caused by ionizing radiation. Studies determined that these genes are important in the genetic stability of DNA. Although the loss of some of these genes does not necessarily confer high levels of sensitivity to radiation, they have been found to represent important components of various pathways of DNA repair. To ensure the integrity of the genome, a complex system of DNA repair was developed. Base excision repair is the first defense mechanism of cells against DNA damage and a major event in preventing mutagenesis. Repair genes may play an important role in maintaining genomic stability through different pathways that are mediated by base excision. In the present study, we examined XRCC1Arg194Trp and XRCC1Arg399Gln polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. Patients who had the allele Trp of the XRCC1Arg194Trp polymorphism had an increased risk of tumor development (OR = 8.80; confidence interval at 95% (95%CI) = 4.37-17.70; P < 0.001), as did the allele Gln of XRCC1Arg399Gln (OR = 1.01; 95%CI = 0.53-1.93; P = 0.971). Comparison of overall survival of patients did not show significant differences. We suggest that XRCC1Arg194Trp and XRCC1Arg399Gln polymorphisms are involved in susceptibility for developing astrocytomas and glioblastomas.     

XRCC1 gene polymorphisms in a population sample and in women with a family history of breast cancer from Rio de Janeiro (Brazil)

The X-ray repair cross-complementing Group1 (XRCC1) gene has been defined as essential in the base excision repair (BER) and single-strand break repair processes. This gene is highly polymorphic, and the most extensively studied genetic changes are in exon 6 (Arg194Trp) and in exon 10 (Arg399Gln). These changes, in conserved protein sites, may alter the base excision repair capacity, increasing the susceptibility to adverse health conditions, including cancer. In the present study, we estimated the frequencies of the XRCC1 gene polymorphisms Arg194Trp and Arg399Gln in healthy individuals and also in women at risk of breast cancer due to family history from Rio de Janeiro. The common genotypes in both positions (194 and 399) were the most frequent in this Brazilian sample. Although the 194Trp variant was overrepresented in women reporting familial cases of breast cancer, no statistically significant differences concerning genotype distribution or intragenic interactions were found between this group and the controls. Thus, in the population analyzed by us, variants Arg194Trp and Arg399Gln did not appear to have any impact on breast cancer susceptibility.     

DNA repair gene polymorphisms affect cytotoxicity in the National Cancer Institute Human Tumour Cell Line Screening Panel

Abstract

Polymorphisms in DNA repair genes have been suggested to increase the risk of cancer and other diseases, but the epidemiological studies are often not consistent, and the results confusing. We have examined the effect of polymorphisms in base and nucleotide excision–repair genes, as well as regulatory and signalling genes, on cytotoxic sensitivity of tumour cell lines used for screening anticancer drugs by the National Cancer Institute. It was found that for the TP53 P72R and ERCC2 D312N polymorphisms, the heterozygous genotype was most sensitive, while for the OGG1 S326C and NOS3 g.?786T?>?C polymorphisms the homozygous-variant genotype was most sensitive. The biggest increase in sensitization was found with the XRCC1 R399Q homozygous dominant genotype. The sensitization was found across a broad range of drugs, indicating the importance of DNA repair responses. It was also found that while the other gene polymorphisms were in Hardy–Weinberg equilibrium, the TP53 P72R heterozygous genotype was relatively depleted. For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype. The cell line with the homozygous-variant genotype had a much poorer repair than the other genotypes, as predicted. The correlation of polymorphisms with cytotoxicity may be an approach to understanding their effects which may be difficult to reveal in epidemiological studies.     

Genetic polymorphisms of the DNA repair gene and risk of nasopharyngeal carcinoma

Context: X-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair, homologous recombination repair, and nucleotide excision repair of DNA repair pathways, respectively. Previous studies have demonstrated that their gene polymorphisms were associated with some cancer susceptibility. Objective and design: To investigate the effect of XPD Lys751Gln, XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 Thr241Met polymorphisms on the risk of nasopharyngeal carcinoma (NPC), a population-based case-control study of 153 NPC patients and 168 healthy controls among Sichuan population was conducted. Results: Our results showed that XRCC1 codon 194 Trp allele was associated with an increased risk of NPC (odds ratio [OR] = 1.828, 95% confidence interval [CI]: 1.286-2.598), and XPD codon 751Gln allele was associated with a borderline decrease of NPC (OR = 0.600, 95% CI: 0.361-1.000); combination analysis showed that individuals with both putative genotypes of XPD codon 751 Lys/Lys and XRCC1 codon 194 Arg/Trp or Trp/Trp have a significantly elevated risk of NPC (OR = 2.708, 95% CI: 1.338-5.478). Conclusion: The results indicated that XRCC1 codon 194 Trp allele and XPD codon 751 Lys allele may be contributing factors in the risk of NPC.     

Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of gamma-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance because of their increased mutagenic/carcinogenic risk.     

Association of theXRCC1 gene polymorphisms in patients with stomach cancer

Genetic instability resulting from mutations in repair genes or denaturation in DNA synthesis has been reported to play an important role in the development of cancer. Through studies of single nucleotide polymorphisms (SNPs), X-ray repair cross-complementing groups 1 (XRCC1), which is an enzyme involved in the process of base repair, has been reported to be linked to the development of cancer. Recently, their roles in other causes of morbidity have also attracted considerable interest. Thus the present case-control study was conducted to determine the possibility of an association betweenXRCC1 polymorphisms and stomach cancer among Korean subjects. The study subjects were composed of 187 patients with stomach cancer, and 206 control subjects with no evidence of any malignancy or premalignant lesions. All the subjects were analyzed for polymorphisms of theXRCC1 gene by means of polymerase chain reaction-restriction fragment length polymorphism.XRCC1 Arg l94Trp(C>T), Arg280His(G>A) and Arg399Gln(G>A) polymorphism. showed no significant link to the development of stomach cancer. Heterozygous mutations ofXRCC1 Argl94Trp (C>T) and Arg280His(G>A) polyroorphisms, bowever, shewed the tendency to be linked to an increased development of intestinal cancer. The haplotypes ofXRCC1 Arg l94Trp(C>T), Arg280His(G>A) and Arg399Gln(G>A) poIymorphisms were associated with an increased risk of development of stomach cancer among individuals with intestinal and diffuse types. We thus conclude that the haplotypes ofXRCC1 polymorphisms are associated with an increased risk of development of stomach cancer.     

XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure

ABSTRACT: BACKGROUND: Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage. FINDINGS: The median (P25-P75) of Olive tail moment was 0.93 (0.58-1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46-1.35) for GA heterozygote and 0.50 (0.43-0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44-1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15-0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage. CONCLUSION: The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.     

No evidence of association between the synonymous polymorphisms in XRCC1 and ERCC2 and breast cancer susceptibility among nonsmoking Chinese

DNA repair proficiency has also been proposed as a potential susceptibility factor for breast cancer. Synonymous polymorphism roles of the DNA repair genes in relation to breast cancer remain largely unknown. Nonsmokers are a good model in which to investigate genetic susceptibility to cancer because they are at low-dose carcinogen exposure. To validate genetic biomarkers of the disease, we explored the effects of the two synonymous polymorphisms [Pro206Pro (rs915927) and Arg156Arg (rs238406)] in the DNA repair genes XRCC1 and ERCC2 at chromosome 19q13.2-3 on breast cancer susceptibility among nonsmoking Chinese. The study recruited 243 patients with breast cancer and 234 cancer-free controls matched to the cases by age (±3years), gender, nonsmoking status and ethnicity. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. No associations were observed between both individual single nucleotide polymorphisms or haplotypes and breast cancer susceptibility. After stratification, no effects were detected for age-dependent effects or menopause status in relation to breast cancer occurrence. No evidence of gene-gene interaction in breast cancer susceptibility was revealed. The two loci were at weak linkage disequilibrium (D' value=0.244, P=0.07). The present data suggest that XRCC1 Pro206Pro and ERCC2 Arg156Arg do not substantially influence breast cancer susceptibility among nonsmoking Chinese.     

Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies.     

Influence of DNA-repair gene variants on the micronucleus frequency in thyroid cancer patients

The role of different DNA-repair genes (OGG1, XRCC1, XRCC2 and XRCC3) on both the spontaneous and the induced frequency of micronuclei (MN) has been studied in the lymphocytes of a group of 114 patients with differentiated thyroid cancer (DTC). Induction of MN was achieved by treatment of the lymphocytes with 0.5 Gy of gamma-radiation.The selected genes are involved in base-excision repair (BER) (OGG1, Ser326Cys; XRCC1, Arg280His and Arg399Gln), and in homologous recombination repair (HRR) (XRCC2, Arg188His and XRCC3, IVS5-14G). Genotyping was carried out by use of the iPLEX (Sequenom) technique.Results indicate that only the OGG1-Ser326Cys polymorphism was able to modulate the MN frequency. This effect was only observed in the spontaneous MN frequency (P = 0.016), but not in the MN frequency induced after irradiation. In addition, a strong correlation was observed between spontaneous and induced MN frequency, which would suggest an underlying genetic background.     

DNA repair gene polymorphisms affect cytotoxicity in the National Cancer Institute Human Tumour Cell Line Screening Panel.

Polymorphisms in DNA repair genes have been suggested to increase the risk of cancer and other diseases, but the epidemiological studies are often not consistent, and the results confusing. We have examined the effect of polymorphisms in base and nucleotide excision-repair genes, as well as regulatory and signalling genes, on cytotoxic sensitivity of tumour cell lines used for screening anticancer drugs by the National Cancer Institute. It was found that for the TP53 P72R and ERCC2 D312N polymorphisms, the heterozygous genotype was most sensitive, while for the OGG1 S326C and NOS3 g.-786T>C polymorphisms the homozygous-variant genotype was most sensitive. The biggest increase in sensitization was found with the XRCC1 R399Q homozygous dominant genotype. The sensitization was found across a broad range of drugs, indicating the importance of DNA repair responses. It was also found that while the other gene polymorphisms were in Hardy-Weinberg equilibrium, the TP53 P72R heterozygous genotype was relatively depleted. For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype. The cell line with the homozygous-variant genotype had a much poorer repair than the other genotypes, as predicted. The correlation of polymorphisms with cytotoxicity may be an approach to understanding their effects which may be difficult to reveal in epidemiological studies.     

A Strong Relationship Between Oral Squamous Cell Carcinoma and DNA Repair Genes

Single nucleotide polymorphisms of DNA repair genes alter protein function and modulate DNA repair efficiency in various cancers. The X-ray repair cross-complementing group (XRCC) is responsible for the repair of DNA base damage and single-strand breaks. The aim of our study was to investigate the association of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms with the susceptibility to develop oral squamous cell carcinoma (OSCC) in Turkish subjects. One hundred eleven patients with OSCC and 148 healthy controls were recruited for the study. Genetic analysis was performed using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). We found that the XRCC1 Arg399Gln Gln/Gln genotype and Gln allele were risk factors for OSCC. Also, Arg/Arg genotype and Arg allele had protective effects against OSCC. Relative to XRCC3 Thr241Met polymorphism, carrying homozygote variants (Thr/Thr and Met/Met) was related with elevated OSCC risk. However, the heterozygote genotype and Thr allele variants were shown to be protective against OSCC. We suggest that XRCC1 Arg399Gln Gln/Gln genotype, Gln allele, and homozygote variants of XRCC3 Thr241Met polymorphism may be a risk factor for predisposition of OSCC in Turkish. In addition, XRCC3 Thr241Met genotype could be associated with tumor size and level of daily smoking.     

Contrasting impact of DNA repair gene XRCC1 polymorphisms Arg399Gln and Arg194Trp on the risk of lung cancer in the north-Indian population

DNA repair forms the most effective defense system against DNA damage. The XRCC1 gene product is implicated in single-strand and base-excision repair mechanisms. Our main aim was to investigate the relationship between the XRCC1 gene with lung cancer on the north-Indian population. Blood samples from 225 North-Indian subjects including 103 newly diagnosed cases and 122 population-based healthy persons were collected. XRCC1 genotypes were detected using a PCR-RFLP technique. The data were analyzed by logistic regression analysis. XRCC1 polymorphisms at codon 399 were found to be protective in the development of lung cancer (OR--0.6, 95% CI--0.46-0.80, p-0.0008). The codon 194 Trp/Trp genotype was associated with a slightly increased risk of lung cancer. When assessed in nonsmokers, only the Arg/Trp genotype of XRCC1 codon 194 was positively associated with lung cancer (OR--2.3, 95% CI--0.77-7.20). Smoking also seemed to significantly interact with the combined genotypes of XRCC1 codon 399 Arg/Gln/Gln/Gln. In conclusion, the results have suggested that the XRCC1 gene might be the risk genotype for lung cancer in this population.     

Association between polymorphisms of XRCC1 and ADPRT genes and ovarian cancer survival with platinum-based chemotherapy in Chinese population

The role of DNA repair gene polymorphisms in cancer development, progression, and response to treatment has received increased attention. We conducted a prospective study to determine whether associations exist between two polymorphisms in XRCC1 and ADPRT and the outcomes of Chinese ovarian cancer patients treated with platinum-based chemotherapy. A total of 335 new cases of ovarian cancer were consecutively collected between May 2005 and May 2007. Follow-up lasted for 4?years, and the outcome measure was survival time. Individuals carrying XRCC1 194Trp/Trp had a longer survival time than did those with the Arg/Arg genotype. Similarly, those carrying XRCC1 399 Gln/Gln genotypes had 0.44-fold the risk of death than those with the Arg/Arg genotype. The combination of XRCC1 194 Trp allele and 399 Gln allele could decrease the death risk of ovarian cancer. In summary, this study is the first to evaluate the associations between polymorphisms in DNA repair gene polymorphism and the risk of ovarian cancer in Chinese population. Our study found a significant association between XRCC1 Arg399Gln and XRCC1 Arg194Trp polymorphism and the clinical outcome of ovarian cancer. Furthermore, studies with larger sample sizes are still needed to confirm these associations in Chinese population.     

DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers

Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]n microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]n microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120 kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873 mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele > or =20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations.     

Interactions between Exposure to Environmental Polycyclic Aromatic Hydrocarbons and DNA Repair Gene Polymorphisms on Bulky DNA Adducts in Human Sperm

Background

Nucleotide excision repair (NER) and base excision repair (BER) are the primary mechanisms for repair of bulky adducts caused by chemical agents, such as PAHs. It is expected that polymorphisms in NER or BER genes may modulate individual susceptibility to PAHs exposure. Here, we evaluate the effects of PAHs exposure and polymorphisms in NER and BER pathway, alone or combined, on polycyclic aromatic hydrocarbon-DNA (PAH–DNA) adducts in human sperm.

Methodology/Principal Findings

Sperm PAH-DNA adducts were measured by immunofluorescent assay using flow cytometry in a sample of 465 infertile adults. Polymorphisms of XPA, XPD, ERCC1, XPF, and XRCC1 were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. The PAHs exposure was detected as urinary 1-hydroxypyrene (1-OHP) levels. In multivariate models adjusted for potential confounders, we observed that XRCC1 5′pUTR -T/C, Arg194Trp, Arg399Gln polymorphisms were associated with increased sperm adduct levels. Furthermore, the stratified analysis indicated that adverse effects of XRCC1 Arg194Trp, Arg399Gln polymorphisms on PAH-DNA adducts were detected only in the high PAHs exposure group.

Conclusions/Significance

These findings provided the first evidence that polymorphisms of XRCC1 may modify sperm PAH-DNA adduct levels and may be useful biomarkers to identify individuals susceptible to DNA damage resulting from PAHs exposure.