DNA Repair Polymorphisms Research Articles

The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde

The International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans because there is "sufficient epidemiological evidence that it causes nasopharyngeal cancer in humans". Genes involved in DNA repair and maintenance of genome integrity are critically involved in protecting against mutations that lead to cancer and/or inherited genetic disease. Association studies have recently provided evidence for a link between DNA repair polymorphisms and micronucleus (MN) induction. We used the cytokinesis-block micronucleus (CBMN assay) in peripheral lymphocytes and MN test in buccal cells to investigate the effects of XRCC3 Thr241Met, ADH5 Val309Ile, and Asp353Glu polymorphisms on the frequency of genotoxicity biomarkers in individuals occupationally exposed to formaldehyde (n = 54) and unexposed workers (n = 82). XRCC3 participates in DNA double-strand break/recombination repair, while ADH5 is an important component of cellular metabolism for the elimination of formaldehyde. Exposed workers had significantly higher frequencies (P < 0.01) than controls for all genotoxicity biomarkers evaluated in this study. Moreover, there were significant associations between XRCC3 genotypes and nuclear buds, namely XRCC3 Met/Met (OR = 3.975, CI 1.053-14.998, P = 0.042) and XRCC3 Thr/Met (OR = 5.632, CI 1.673-18.961, P = 0.005) in comparison with XRCC3 Thr/Thr. ADH5 polymorphisms did not show significant effects. This study highlights the importance of integrating genotoxicity biomarkers and genetic polymorphisms in human biomonitoring studies.

Polymorphisms of DNA repair and oxidative stress genes in B-cell lymphoma patients

The purpose of the study was to investigate the possible association between ERCC2 rs28365048, ERCC5 rs17655, XRCC3 rs861539 and NOS2A rs2297518 polymorphisms with B-cell lymphoma. The study was conducted on 189 patients with CD20+ B-cell lymphoma and 193 controls. The genotype frequencies were compared in the patient and control groups using quantitative polymerase chain reaction, based on allelic discrimination analysis. Our results indicated that variation in NOS2A may be significant in B-cell lymphoma in a population ≥50 years old (OR=2.15; 95% CI, 1.17-3.92; P=0.013). No association was observed between variations in ERCC2, ERCC5, XRCC3 and B-cell lymphoma in the studied population. Our finding of an association between age and NOS2A polymorphisms in lymphoma is unique and requires additional studies. The results concerning ERCC2, ERCC5 and XRCC3 variations add additional data to studies on genetic polymorphisms in the DNA repair pathway.

DNA Repair Polymorphisms and Treatment Outcomes of Patients with Malignant Mesothelioma Treated with Gemcitabine-Platinum Combination Chemotherapy

Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy. In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model. There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity. Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.

Genetic Variations in XRCC1 Gene in Sporadic Head and Neck Cancer (HNC) Patients

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. Polymorphisms in the DNA repair gene XRCC1 have been indicated to have a contributive role in DNA adduct formation and an increased risk of cancer development. 300 head and neck cancer patients and 150 controls were included in this study. PCR-single-strand conformation polymorphism and DNA sequencing were used to analyze the whole exonic region of XRCC1 in head and neck cancer patients. Sequence analysis revealed two missense and two silent mutations in our study. Frequency of silent mutations; Pro206Pro (rs915927) and Gln632Gln (rs3547) was calculated as 0.16 (16%) and 0.30 (30%) respectively. Whereas, the frequency of missense mutations; Arg399Gln (rs25487) and Tyr576Asn (rs2307177) was calculated as 0.27 (27%) and 0.28 (28%) respectively. In our study, incidence of these mutations was found higher in larynx cancer (p < 0.005) as compared to oral cavity and pharynx cancer. Our finding suggests that the polymorphic XRCC1 gene may contribute to risk of developing head and neck cancer. To our knowledge, this is the first report that XRCC1 is associated with increased risk of head and neck cancer in a Pakistani population.

1244P - Effect of Germline Polymorphisms of DNA Repair Genes on Chemotherapy Outcome in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

ABSTRACT Background The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5′UTR, 2R G > C SNP, 3R G > C SNP) and methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p = 0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p = 0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p = 0.005), smokers (p = 0.036) and age Conclusions ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age Disclosure All authors have declared no conflicts of interest.

Multi‐loci analysis reveals the importance of genetic variations in sensitivity of platinum‐based chemotherapy in non‐small‐cell lung cancer

Polymorphisms in DNA repair and apoptotic pathways may cause variations in chemosensitivity of non-small-cell lung cancer (NSCLC) through complex gene-gene and gene-environment interactions. A total of 200 advanced NSCLC patients who received platinum-based chemotherapies were recruited. The short-term clinical outcomes were classified as chemosensitive group, including complete remission (CR) and partial remission (PR), and chemoresistant group, namely stable disease (SD) and progression disease (PD) at the end of treatment. We applied multifactor dimensionality reduction (MDR), classification and regression tree (CART) and traditional logistic regression (LR) to explore high-order gene-gene and gene-environment interactions among 11 functional single nucleotide polymorphisms (SNPs), smoking status, cancer stages and treatment regimens in the response to chemotherapy. Multi-loci analyses consistently indicated that interactions among XRCC1 Arg194Trp, XPC PAT, FAS G-1377A, and FASL T-844C were associated with sensitivity to platinum-based chemotherapy. In MDR analysis, the four-factor model yielded the highest test accuracy of 0.72 (permutation P = 0.001). In CART analysis, these four SNPs were the determinant nodes of the growth of regression tree. Patients carrying XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed completely no response to platinum, whereas patients with XRCC1 194Trp allele and XPC PAT +/+ had 68.8% response rate to platinum. In LR analysis, a significant gene-dosage effect was detected along with the increasing number of favorable genotypes of these four polymorphisms (P trend = 0.00002). Multi-loci analysis reveals the importance of genetic variations involved in DNA repair and apoptotic pathways in sensitivity of platinum-based chemotherapy in NSCLC.

DNA repair polymorphisms influence the risk of second neoplasm after treatment of childhood acute lymphoblastic leukemia

Patients treated for childhood acute lymphoblastic leukemia (ALL) are considered to be at increased risk of developing second neoplasm. The aim of our study was to identify DNA repair polymorphisms contributing to the risk of second neoplasm in clinically well-characterized Slovenian patients treated for childhood ALL. Pediatric patients diagnosed with ALL between 1971 and 2001 were included in the study. According to the identified clinical risk factors for second neoplasm, a matched set of cases with second neoplasm and controls was selected and genotyped for 11 DNA repair polymorphisms. Among 359 pediatric patients with ALL, 20 second neoplasms were observed. The dose of radiotherapy (P = 0.011), administration of epipodophyllotoxins (P = 0.006), and the dose of anthracyclines (P < 0.001) showed a significant association with the risk of second neoplasm. Among genetic factors, we observed a significant association of NBN 1197G allele with increased risk of second neoplasms (RR = 4.36; 95 % CI: 1.19-15.98; P = 0.026), while the risk was decreased in carriers of XRCC3-316G allele compared with patients with wild-type genotype (RR = 0.20; 95 % CI: 0.04-0.99; P = 0.049). Our results suggest an important role of NBN 1197A>G and XRCC3-316A>G polymorphisms in the development of second neoplasm in patients treated for childhood ALL.

EGFRexon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

Effect of germline polymorphisms of DNA repair genes on chemotherapy outcome in advanced non-small cell lung cancer (NSCLC) patients.

e18057 Background: The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods: A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5’UTR, 2R G&gt;C SNP, 3R G&gt;C SNP) and Methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p=0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p=0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p=0.005), smokers (p=0.036) and age &lt;70 years (p=0.012). Patients with A/A or A/C genotypes in codon 751 in XPD had a trend to longer median OS than those C/C (p=0.09). No differences in median PFS were observed. No association between TS and MTHFR polymorphisms and outcome was found in overall population. Conclusions: ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age &lt;70 subgroups.

Association of GSTT1 polymorphism with acute myeloid leukemia risk is dependent on smoking status

Genetic polymorphisms in drug-metabolizing, DNA repair and multidrug resistance genes affect the risks for many cancers. We analyzed 21 polymorphisms in 17 genes in these pathways to evaluate their association with the risk of acute myeloid leukemia (AML) and to examine whether smoking modifies these associations in a population-based study in Korea (415 cases, 1700 controls). We found marginal associations between the risk of AML and CYP1A1 1188, and XRCC1 194, ERCC1 IVS5 + 33 and WRN 787 polymorphisms. However, when we performed the analysis according to smoking exposure, we found a stronger association for ERCC1 only in the non-smoking population (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.60–0.91, p = 0.004), while we found the GSTT1-null genotype to be associated with an increased risk of AML in ever-smokers (OR = 1.51; 95% CI = 1.06–2.15, p = 0.02). These results indicate that ERCC1 and GSTT1-null polymorphisms may have an effect on AML risk that is dependent on smoking exposure.

DNA Repair Polymorphisms in B-cell Chronic Lymphocytic Leukemia in Sufferers of Chernobyl Nuclear Power Plant Accident

An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.

Association Between DNA-repair Polymorphisms and Survival in Pancreatic Cancer Patients Treated with Combination Chemotherapy

This multicenter study evaluated the association of 11 candidate polymorphisms in eight genes with outcome of pancreatic cancer patients treated with the equivalent polychemotherapeutic regimens: cisplatin/epirubicin/capecitabine/gemcitabine, cisplatin/docetaxel/capecitabine/gemcitabine and gemcitabine/capecitabine plus epirubicin/cisplatin intra-arterial infusion. Towards this end, polymorphisms were assessed in DNA from 122 pancreatic cancer stage-III/IV patients, and their associations with toxicity/response and progression-free survival (PFS) and overall survival were evaluated using Pearson-χ(2) and log-rank test. Patients harboring XPD Gln751Gln, XPD Asp312Asn + Asn312Asn or XRCC1 Arg399Gln + Gln399Gln genotypes had a worse prognosis. XPD Gln751Gln (hazard ratio: 1.9; p = 0.003), as well as a combination of over two risk genotypes (hazard ratio: 2.7; p < 0.001), emerged as independent predictors for death risk at multivariate analysis. No correlations were observed with toxicity. Conversely, XPD Gln751Gln was associated with shorter PFS, while the lack of association with overall survival/PFS in gemcitabine monotherapy-treated patients suggested its role only for platinum-based regimens. Polymorphisms of DNA-repair genes appear to be candidate biomarkers of primary resistance to gemcitabine/cisplatin-based polychemotherapeutic regimens. The relatively small sample size, coupled with the retrospective and exploratory design of the present study, imply that these results should be considered as hypothesis generators, and should be further evaluated in larger and adequately designed retrospective/prospective studies.

Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia

Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL.

Genetic Polymorphisms of DNA Repair and Inflammatory Responses as Determinants of Late Toxicity in Prostate Cancer Patients Who Received Radiotherapy in a Randomized Trial

We pilot tested whether single nucleotide polymorphisms (SNPs) in DNA repair and inflammatory responses are associated with adverse genitourinary (GU) and/or gastrointestinal (GI) late toxicities in prostate cancer patients enrolled in a randomized external beam radiotherapy hypofractionation clinical trial performed between 2002 and 2006 at the Fox Chase Cancer Center.

Impact of XPC LL Variant on Head and Neck Cancer Survival

Objective: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Several genetic polymorphisms have been shown to increase the risk of HNSCC. In this study we investigated how these genetic variations affect survival of HNSCC patients. Method: DNA from blood lymphocytes of 180 HNSCC patients were analyzed for polymorphisms of DNA repair and carcinogen-metabolizing genes. The association between polymorphisms with time to recurrence and survival were analyzed. Results: There was no association between the variants analyzed and time to disease recurrence. However, increased survival that approached statistical significance was observed in patients with XPC LL genotype. They had a longer survival compared with patients with XPC LS and XPC SS genotypes (mean survival LL = 283 months, LS = 60 months, SS = 72 months; log rank P = .06), especially in men ( P = .047). Conclusion: The genetic variant XPC LL of the DNA repair gene XPC is associated with increased survival of HNSCC in those patients managed with treatment modalities that target DNA (ie, cisplatin and radiation). Larger and more comprehensive studies are needed to validate these findings.

European ancestry and polymorphisms in DNA repair genes modify the risk of melanoma: A case–control study in a high UV index region in Brazil

UV radiation is the major environmental factor related to development of cutaneous melanoma. Besides sun exposure and the influence of latitude, some host characteristics such as skin phototype and hair and eye color are also risk factors for melanoma. Polymorphisms in DNA repair genes could be good candidates for susceptibility genes, mainly in geographical regions exposed to high solar radiation. Evaluate the role of host characteristics and DNA repair polymorphism in melanoma risk in Brazil. We carried out a hospital-based case-control study in Brazil to evaluate the contribution of host factors and polymorphisms in DNA repair to melanoma risk. A total of 412 patients (202 with melanoma and 210 controls) were analyzed regarding host characteristics for melanoma risk as well as for 11 polymorphisms in DNA repair genes. We found an association of host characteristics with melanoma development, such as eye and hair color, fair skin, history of pigmented lesions removed, sunburns in childhood and adolescence, and also European ancestry. Regarding DNA repair gene polymorphisms, we found protection for the XPG 1104 His/His genotype (OR 0.32; 95% CI 0.13-0.75), and increased risk for three polymorphisms in the XPC gene (PAT+; IV-6A and 939Gln), which represent a haplotype for XPC. Melanoma risk was higher in individuals carrying the complete XPC haplotype than each individual polymorphism (OR 3.64; 95% CI 1.77-7.48). Our data indicate that the host factors European ancestry and XPC polymorphisms contributed to melanoma risk in a region exposed to high sun radiation.

Genetic polymorphisms in DNA repair and oxidative stress pathways associated with malignant melanoma susceptibility

BackgroundBase excision repair (BER) and nucleotide excision repair (NER) pathways eliminate a wide variety of DNA damage, including UV photoproducts. The ability of each individual to repair DNA damage following different causes might explain at least in part the variability in cancer susceptibility. Moreover, inflammatory response to UV exposure may further contribute to skin carcinogenesis by oxidative stress mechanisms. Single nucleotide polymorphisms in genes encoding various DNA-repair enzymes and oxidative stress factors may be candidate low-penetrance variants with a role in susceptibility to different cancers, particularly in those with aetiologies linked to environmental exposure, such as malignant melanoma (MM). MethodsIn this case–control study, 684 Spanish sporadic MM patients and 406 cancer-free control subjects were included and the role of 46 polymorphisms belonging to 16 BER and NER genes as well as 11 genes involved in oxidative stress processes were investigated. ResultsOne polymorphism was identified to be individually associated with MM in the Spanish population. The variant was found in the NOS1 oxidative stress gene (rs2682826; p-value=0.01). These results suggest a putative role of oxidative stress processes in the genetic predisposition to melanoma. ConclusionTo the authors’ knowledge, this is the largest DNA repair-related SNP study in melanoma risk conducted in the Spanish population up to now. Furthermore, it also represents a comprehensive genetic study of several oxidative stress polymorphisms tested in relation to MM susceptibility.

Abstract 5618: Polymorphisms in DNA repair genes are associated with endometrial cancer risk among Japanese women

Abstract Common polymorphisms in DNA repair genes may affect an individual's capacity to repair damaged DNA. Although many former studies have reported an association between several types of cancers and DNA repair polymorphism, the association with endometrial cancer (EC) risk has not been investigated fully, especially in Asian population. To examine the association between DNA repair polymorphisms and postmenopausal EC risk, we conducted a case-control study with 91 EC cases (59 endometrioid adenocarcinoma and 32 other types of carcinoma) and 261 non-cancer female controls from database of Hospital based Epidemiologic Research Program at Aichi Cancer Center. We examined 16 coding SNPs (single nucleotide polymorphism) of 12 DNA repair genes (OGG1, MUTYH, XRCC1, APE1, ADPRT, XPA, XPC, XPD, ERCC1, RAD23B, XPG, ERCC6) by TaqMan Methods. We surveyed lifestyle/environmental information by self-administered questionnaire. Impact of each SNPs on EC risk was evaluated by multivariate unconditional logistic regression models. Further, we examined the gene-gene interaction. We observed significant association between EC risk and rs1799782 (C&amp;gt;T, Arg194Trp) of XRCC1 [CT: Odds ratio (OR) = 1.74, 95% confidence interval (95% CI) = 0.99-3.04, TT: OR = 2.76, 95% CI = 1.23-6.16; trend p = 0.007]; rs25487 (G&amp;gt;A, Arg399Gln) of XRCC1 [GA: OR = 0.66, 95% CI = 0.39-1.12, AA: OR = 0.15, 95% CI = 0.02-1.16; trend p = 0.019]; rs1136410 (T&amp;gt;C, Val762Ala) of ADPRT [TC: OR = 1.49, 95% CI = 0.84-2.64, CC: OR = 1.92, 95% CI = 0.88-4.18; trend p = 0.076]; and rs17655 (G&amp;gt;C, Asp1104His) of XPG [GC: OR = 0.68, 95% CI = 0.39-1.21, CC: OR = 0.54, 95% CI = 0.26-1.12; trend p = 0.082]. Although both XRCC1 and ADPRT involve in base excision repair, gene-gene interaction of these polymorphisms were not significant; the interaction p between rs1799782 and rs25487 was 0.687; that between rs25487 and rs1136410 was 0.328. In conclusion, we found significant association between EC risk among postmenopausal Japanese women and DNA repair polymorphisms. Gene-gene interactions between XRCC1 and ADPRT were not significant. These results suggests that DNA repair polymorphisms might be associated with etiology of EC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5618. doi:10.1158/1538-7445.AM2011-5618

Abstract 2739: DNA repair genotype-phenotype correlation and interplay between different DNA repair pathways

Abstract Individual DNA repair capacity is modulated by the genetic background to which hundreds of single nucleotide polymorphisms (SNPs) or haplotype combinations in DNA repair genes are likely to contribute. A large number of studies have been published on the association between DNA repair gene polymorphisms and cancer risk, whereas only few small studies investigated the relation between DNA repair phenotypic assays and cancer risk or DNA repair polymorphisms. In order to identify functional SNPs/haplotypes modulating DNA repair phenotypes and to investigate their potential impact on cancer risk, we have performed a genotype-phenotype correlation study evaluating levels of DNA damage and DNA repair capacity in blood cells treated at low doses of different DNA damaging agents. We investigated the association between genotypes/haplotypes and the DNA repair capacity measured with the following DNA repair phenotypic assays on cryopreserved lymphocytes from 225 healthy individuals: Comet assay after treatment with BPDE, phosphorylation of histone H2AX after treatment with γ-rays, OGG1 glycosylase activity, OGG1 and ERCC1 expression levels. Sixty-five DNA repair genes and a total of 768 SNPs have been selected and analysed on the 225 DNA samples by using a custom GoldenGate SNP chip (Illumina). Genotype-phenotype correlation analysis identified some new possible functional variants and haplotypes. We also tested gene-gene interactions, comparing results with existing prior knowledge from different publicly available databases and crossing functional evidence with information on gene expression levels and protein-protein interaction. A confirmation of some already described interplays between different DNA repair pathways have been obtained from SNP analysis and a suggestion of new possible cross-talks have been identified that need further experimental validation. Our results can contribute to identify subjects carrying combinations of less efficient DNA repair variants/haplotypes possibly at increased cancer risk or who can better benefit from anti-cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2739. doi:10.1158/1538-7445.AM2011-2739

Abstract 3918: Haploinsufficiency of MRE11A reduces DNA repair capacity in bronchial epithelial cells in response to Bleomycin and BPDE

Abstract Reduced DNA repair capacity (DRC) and polymorphisms in genes involved in the requisite repair pathways are associated with increased risk for lung cancer and promoter hypermethylation. A SNP (rs7117042) was identified in MRE11A that resulted in a 30% reduction in gene transcription and was associated with promoter methylation in sputum from cancer-free smokers. In vitro studies have also demonstrated that formation of DNA double strand breaks (DSB) can lead to gene promoter methylation. The purpose of this study was to identify genes in the DSB repair pathway that may be rate limiting for DNA repair in response to DNA damage and ultimately assess their effect on transformation and promoter methylation. A model for haploinsufficiency was created to simulate germ line sequence variation in the MRE11A, NBS, and XRCC3 gene by shRNA stable knockdown in immortalized human bronchial epithelial cells (HBEC2 and HBEC13). The clones with 50% and 75% knockdown of target genes were selected and cell lines were exposed to increasing doses of bleomycin and BPDE respectively with DRC determined by formation of micronuclei. MRE11A knockdown reduced DRC by 2- and 2.5-fold following exposure to BPDE and bleomycin, respectively compared to parental cell lines. DRC also varied by degree of gene knock down. Studies were extended to address the functional impact of the MRE11a SNP on DRC by challenging lymphocytes wild type or heterozygote for this SNP to bleomycin. A 30-40% reduction in DRC was seen in heterozygotes compared to wild type. Studies are ongoing to address the effect of chronic carcinogen exposure of HBECs with knock down of MRE11a on transformation efficiency and induction of gene promoter hypermethylation. These studies support a important role for MRE11A in the response of the cell to double-strand break damage. Supported by NIH R01 ES015262. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3918. doi:10.1158/1538-7445.AM2011-3918