XRCC1 Genotypes Research Articles

Polymorphisms and haplotypes of DNA repair and xenobiotic metabolism genes and risk of DNA damage in Chinese vinyl chloride monomer (VCM)-exposed workers

In this case–control study, we investigated the association between DNA damage and genetic susceptibility among vinyl chloride monomer (VCM)-exposed workers. The cumulative exposure dose of VCM was calculated based on the workers’ duration of exposure and the geometric mean concentration of VCM in the workplace. DNA damage to peripheral blood lymphocytes was measured by single cell gel electrophoresis (SCGE) assay, and single nucleotide-polymorphisms (SNPs) in xenobiotic metabolism and DNA repair genes were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Univariate analysis showed that the CYP2E1 c1c2/ c2c2 and XPD751 Lys/ Gln and Gln/ Gln genotypes were significantly associated with the levels of DNA damage ( P < 0.01 and 0.05, respectively). Further logistic regression analysis showed a significant association between CYP2E1 c1c2/ c2c2 and DNA damage, and risk of having increased levels of DNA damage was more pronounced in those individuals having XRCC1 194 mutant genotypes and/or XPD751 Lys/ Gln and Gln/ Gln genotypes. Although most of the XPD and XRCC1 haplotypes did not show any significant difference, the XRCC1 haplotype Trp194–Arg280 was significantly over-represented in the case group ( P < 0.05; OR 2.09; 95% CI: 1.07–4.06) than in controls. Overall, our data suggest that the genotypes of CYP2E1, XRCC1 194, and XPD 751 were associated with the level of DNA damage and may contribute to individual sensitivity to DNA damage induced by VCM in the workplace.

ERCC22251A&gt;C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: A preliminary study

BackgroundEarly relapse in colorectal cancer (CRC) patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage) and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes.MethodsSix gene polymorphisms functional in drug-metabolism – GSTP1 Ile105Val, ABCB1 Ile1145Ile, MTHFR Ala222Val, TYMS double (2R) or triple (3R) tandem repeat – and DNA-repair genes – ERCC2 Lys751Gln and XRCC1 Arg399Gln – were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0) or III (any T N1 and 2 M0) and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU) and leucovorin (LV). The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated.ResultsIn this study, the distributions of GSTP1 (P = 0.003), ABCB1 (P = 0.001), TYMS (P < 0.0001), ERCC2 (P < 0.0001) and XRCC1 (P = 0.006) genotypes in the Asian population, with the exception of MTHFR (P = 0.081), differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype ERCC2 2251A>C (P = 0.006), tumor invasion depth (P = 0.025), lymph node metastasis (P = 0.011) and cancer stage (P = 0.008) were significantly correlated with early relapse. Patients carrying the ERCC2 2251AC or2251CC genotypes had a significantly increased risk of early relapse (OR = 3.294, 95% CI, 1.272–8.532).ConclusionWe suggest that ERCC2 2251A>C alleles may be genetic predictors of early CRC relapse.

The investigation of DNA repair polymorphisms with histopathological characteristics and hormone receptors in a group of Brazilian women with breast cancer

The association of tumor differentiation and estrogen receptor expression with the prognosis of breast cancer has been well established. Nevertheless, little is yet reported about the association of morphological characteristics of the tumor, estrogen receptor status and polymorphisms in low penetrance genes. The aim of the present study was to investigate a possible association between DNA repair gene polymorphisms (XRCC1, XPD, XRCC3, and RAD51) with histological type, grade and hormone receptor expression in a series of breast cancers. A cross-sectional study was carried out to evaluate 94 women with breast carcinoma, who had already been selected and included in a study on the association of DNA repair gene polymorphisms. For immunohistochemistry, formalin-fixed, paraffin-embedded tissue samples from breast tumors were consecutively retrieved from the histopathology files of our institution. DNA obtained from blood samples of the same patients was investigated for the presence of the following polymorphisms: Arg-399Gln located in the XRCC1 gene; 135C/G located in the RAD51 gene; Lys751Gln located in the XPD gene and Thr241Met located in the XRCC3 gene. Polymorphisms were considered to be independent variables and hormone receptor expression and the morphological characteristics of the tumors comprised the dependent variables. No statistically significant association was found between gene polymorphisms and hormone receptor status. The association between XRCC1-Arg399Gln polymorphism and ductal carcinoma was statistically significant (P = 0.02). The association of the XPD-Lys751Gln polymorphism with histological grade was also tatistically significant (p = 0.05). In conclusion, the XRCC1 genotype was found to be associated with ductal carcinoma histotypes and XPD genotype with low histological grade, which is the most frequent pattern of sporadic breast carcinomas.

HOGG1326, XRCC1399 and XRCC3241 polymorphisms influence micronucleus frequencies in human lymphocytes in vivo

A pooled analysis of five biomonitoring studies was performed to assess the influence of hOGG1(326), XRCC1(399) and XRCC3(241) gene polymorphisms on micronuclei (MN) frequency in human peripheral blood lymphocytes, as measured by the ex vivo/in vitro cytokinesis-block micronucleus (CBMN) assay. Each study addressed a type of occupational exposure potentially able to induce DNA strand breakage (styrene, ionising radiation, cobalt/hard metal, welding fumes and inorganic arsenite compounds), and therefore MN, as a result of base excision repair and double-strand break repair deficiencies. The effect of genotype, age, exposure to genotoxic agents and smoking habit on MN induction was determined using Poisson regression analysis in 171 occupationally exposed male workers and in 132 non-exposed male referents. The analysis of genotype-genotype, genotype-smoking and genotype-exposure interactions by linear combinations of parameters showed significantly higher MN frequencies in the following subsets: (i) occupationally exposed workers carrying either the Thr/Thr or the Thr/Met XRCC3(241) genotypes compared to their referent counterparts (P < 0.001) and (ii) carriers of the Met/Met XRCC3(241) genotype compared to Thr/Thr XRCC3(241) carriers, as far as they are non-exposed and bear the variant (Ser/Cys or Cys/Cys) hOGG1(326) genotype (P < 0.01). Significantly lower MN frequencies were observed in carriers of the variant hOGG1(326) genotype compared to Ser/Ser hOGG1(326) carriers in the subgroup of non-smokers with Thr/Thr XRCC3(241) genotype (P < 0.01). Stratified analysis by occupational exposure showed a significant MN increase with smoking in occupationally exposed carriers of the Arg/Gln XRCC1(399)genotype (P < 0.001). In contrast, a significant MN decrease with smoking was observed in referents carrying the Ser/Ser hOGG1(326) genotype (P < 0.01). These findings provide evidence that the combination of different DNA repair genes and their interaction with environmental genotoxic agents may modulate MN induction. Understanding the complexity of the relationships between exposure, DNA repair and MN frequencies require larger scale studies and complementary biomarkers.

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group

Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-S-transferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA double-strand breaks (etoposide, daunomycin), compared with anti-metabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.

XRCC2 and XRCC3 Gene Polymorphismand Risk of Pancreatic Cancer

XRCC2 and XRCC3 are key components of the homologous recombination (HR) machinery that repairs DNA double-strand breaks. We hypothesized that the altered HR repair capacity conferred by single nucleotide polymorphisms (SNPs) would modify individual susceptibility to sporadic pancreatic cancer. In a hospital-based case-control study, genomic DNA and exposure information was obtained from 468 patients with pathologically confirmed pancreatic adenocarcinoma and 498 frequency-matched healthy controls at M.D. Anderson Cancer Center during January 2000 to September 2006. Genotypes of XRCC2 31479 G>A (Arg188His) and XRCC3 17893 A>G and 18067 C>T (Thr241Met) were determined using the Masscode technology. Unconditional logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) in non-Hispanic whites (408 cases and 449 controls). The distribution of genotype frequencies was not different between cases and controls. We observed a significant effect modification between XRCC2 polymorphism and smoking status and pack-year of smoking in modifying pancreatic cancer risk (P value for interaction 0.02 and 0.05, respectively). Compared with never-smokers carrying the XRCC2 Arg188Arg genotype, the OR (95% CI) for individuals carrying the (188)His allele was 2.32 (1.25-4.31) among ever-smokers, 1.43 (0.59-3.48) among light smokers (< or = 22 pack-years), and 3.42 (1.47-7.96) among heavy smokers (> or =22 pack-years). The two XRCC3 SNPs are in strong linkage disequilibrium, but there was no suggestive association between XRCC3 genotype and the risk of pancreatic cancer. XRCC2 Arg188His polymorphism may be one of the genetic modifiers for smoking-related pancreatic cancer.

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

Polymorphisms at N-acetyl transferase 2 locus (NAT2) lead to slow, intermediate and rapid acetylation properties of the enzyme. Improper acetylation of heterocyclic and aromatic amines, present in tobacco, might cause DNA adduct formation. Generally, DNA repair enzymes remove these adduct to escape malignancy. But, tobacco users carrying susceptible NAT2 and DNA repair loci might be at risk of oral leukoplakia and cancer. In this study, 389 controls, 224 leukoplakia and 310 cancer patients were genotyped at 5 polymorphic sites on NAT2 and 3 polymorphic sites on each of XRCC1 and XPD loci by PCR-RFLP method to determine the risk of the diseases. None of the SNPs on these loci independently could modify the risk of the diseases in overall population but variant genotype (Gln/Gln) at codon 399 on XRCC1 and major genotype (Lys/Lys) at codon 751 on XPD were associated with increased risk of leukoplakia and cancer among slow acetylators, respectively (OR = 4.2, 95% CI = 1.2-15.0; OR = 1.6, 95% CI = 1.1-2.3, respectively). Variant genotype (Asn/Asn) at codon 312 on XPD was also associated with increased risk of cancer among rapid and intermediate acetylators (OR = 1.9, 95% CI = 1.2-2.9). Variant C-G-A haplotype at XRCC1 was associated with increased risk of leukoplakia (OR = 1.7, 95% CI = 1.2-2.4) but leukoplakia and cancer in mixed tobacco users (OR = 3.1, 95% CI = 1.4-7.1, OR = 2.4, 95% CI = 1.1-5.4, respectively) among slow acetylators. Although none of the 3 loci could modulate the risk of the diseases independently but 2 loci in combination, working in 2 different biochemical pathways, could do so in these patient populations.

Pharmacogenetic Predictors of Toxicity in Dose-Intensive Therapy for Pediatric Advanced-Stage Hodgkin's Lymphoma.

Outcomes for patients with advanced-stage Hodgkin's lymphoma (HL) remain suboptimal, as dose-intensified regimens produce relatively high cure rates at the cost of increased short- and long-term complications. Prospectively identifying the subset of patients who are at risk of therapy-related complications would allow refinement of treatment regimens. We hypothesized that functional polymorphisms in chemotherapy drug metabolizing enzymes will predict the risk of toxicity for pediatric patients with advanced-stage HL. Glutathione-S-transferase T1 (GSTT1) and glutathione-S-transferase M1 (GSTM1) participate in protection against oxidative damage. Previously, we demonstrated that genetic deletion of these enzymes, a common population polymorphism, increase the risk of regimen-related mortality in pediatric patients with acute myeloid leukemia. The human DNA repair gene XRCC1 is involved in the repair of DNA single-strand breaks, generated in response to alkylating agents and ionizing radiation, and a frequent single nucleotide polymorphism with reduced function (codon 399 arginine to glutamine substitution) has been associated with an increased risk of secondary malignancy. We examined the effects of polymorphic alleles of GSTT1, GSTM1 and XRCC1 on the risk of toxicity in 72 pediatric patients receiving chemotherapy for advanced stage (clinical stage IV, stages IIB/IIIB with bulk disease) Hodgkin's lymphoma. Therapy consisted of intensified BEACOPP induction (4 cycles of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) followed by response-adapted continuation therapy. This regimen (Children's Cancer Group Study 59704) is associated with a 4-year event-free survival rate of 95%. We found that polymorphic low/loss of function alleles were associated with an increased frequency of hematologic toxicities. We observed an increased frequency of therapy-associated thrombocytopenia in patients with absent GSTM1 (79% pts with grade 3/4 thrombocytopenia when GSTM1 absent vs 55% when present, p=0.0491). There was also an increased frequency of infection with neutropenia in patients with absent GSTT1 (57% when GSTT1 absent vs 23% when present, p=0.0522). The XRCC1 variant allele was associated with increased frequency of infection with neutropenia in a dose-dependent fashion (glutamine/glutamine: 67% with toxicity, arginine/glutamine: 27%, arginine/arginine: 13%; p= 0.0308). Similarly XRCC1 genotype was associated with increased frequency of thrombocytopenia (glutamine/glutamine: 67%, glutamine/arginine: 35%, arginine/arginine: 17%; p= 0.0498). Conclusion: These results, representing the only reported data in HL, suggest that deletion of GSTT1 and GSTM1, and variant alleles of XRCC1 may influence risk for toxicity with intensive BEACOPP chemotherapy. Prospective studies in future cohorts are needed to confirm these observations.

402 POSTER Biological and clinical significance of fatty acid synthase overexpression in cancer

Styrene oxide (SO), ethylene oxide (EO) and gamma-radiation (G) are agents with a well-described metabolism and genotoxicity. EPHX1 and GSTs play an important role in the detoxification of electrophiles and oxidative stress. Enzymes involved in base excision repair (hOGG1, XRCC1), in rejoining single strand breaks (XRCC1) and in repair of cross-links and chromosomal double strand breaks (XRCC3) might have an impact on genotoxicity as well.In this study we assessed the dose-dependent effect of genetic polymorphisms in biotransforming (EPHX (Tyr113/His113 and His139/Arg139), GSTP1 (Ile105/Val105), GSTM1 and GSTT1) and DNA repair enzymes (hOGG1 (Ser326/Cys326), XRCC1 (Arg194/Trp194, Arg280/His280, Arg399/Gln399), XRCC3 (Thr241/Met241)) on the induced genotoxicity.Peripheral blood mononuclear cells from 20 individuals were exposed to 3 doses per agent (+control). Genotoxicity was evaluated by measuring comet tail length (TL) and micronucleus frequencies in binucleated cells (MNCB).Dose-dependent DNA damage was found for all agents and end-points, with the exception of MNCB induced by EO. Repeated measure ANOVA revealed a significant contribution of hOGG1 and XRCC3 genotypes to the inter-individual variability of TL and MNCB in cells exposed to EO and G. Homozygous hOGG1326 wild cells showed significantly lower EO-induced TL than the heterozygous cells. Significantly higher TL and MNCB were found in EO-exposed cells carrying the XRCC3241Met variant and the influence on TL was more pronounced at higher dose. In G-irradiated cells, TL was significantly higher in the hOGG1326 homozygous wild types compared with mutated genotypes. The influence of hOGG1326 on TL was borderline dose-dependent.We conclude that the influence of genetic polymorphisms of enzymes involved in DNA repair on induced genotoxicity depends on exposure dose.

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

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

The polymorphisms of GSTM1, GSTT1, HYL12, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China

High incidence rates of hepatocellular carcinoma (HCC) in Guangxi, China, are primarily due to heavy aflatoxin B1 (AFB1) exposure via corn and groundnut consumption. This study was designed to examine the polymorphisms associated of three carcinogen-metabolizing genes (namely: GSTM1, GSTT1, and HYL1*2) and one DNA-repair gene (namely: XRCC1), and investigate their role as susceptibility markers for HCC. We conducted a case-control study including 257 cases of cancer and 649 hospital-based age, sex, ethnicity, and hepatitis B virus infection-matched controls to examine the role of genetic polymorphisms of four genes (GSTM1, GSTT1, HYL1*2, and XRCC1) in the context of HCC risk for the Guangxi population. Genomic DNA isolated from 2ml whole blood was used to genotype GSTM1, GSTT1, HYL1*2, and XRCC1 by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. GSTT1-null genotype was not significantly associated with the risk of HCC, but GSTM1-null genotype [adjusted odds ratio (OR)=2.29, 95% confidence interval (CI)=1.59-3.31], HYL1*2 genotypes with 113 His allele (namely: YH/HH, adjusted OR=2.55, CI=1.78-3.65), and XRCC1 genotypes with 399 Gln allele (namely: AG/GG, adjusted OR=2.47, CI=1.72-3.54) increased the HCC risk. Compared with those individuals who did not express any putative risk genotypes as reference (OR=1), individuals featuring all of the putative risk genotypes [GSTM1-null, HYL1*2-YH/HH, and XRCC1-AG/GG] did experience a significantly greater cancer risk (adjusted OR=10.83, CI=5.44-21.59, P(interaction)<0.01). Additionally, the risk of HCC did appear to differ more significantly among individuals featuring risk genotypes and high-level or long-term AFB1 exposure, whose adjusted ORs (CIs) were 52.44 (17.51-157.08) and 326.93 (38.58-2770.52), respectively. The results suggest that carcinogen metabolism and DNA-repair pathways may simultaneously modulate the risk of HCC for Guangxi population, and, particularly for these having high-level or long-term AFB1 exposure.

Lycopene Intake and Prostate Cancer Risk: Effect Modification by Plasma Antioxidants and the XRCC1 Genotype

: Lycopene has been associated with reduced prostate cancer risk, although the results of epidemiological studies have varied. We hypothesize that an effect of lycopene may be modified by XRCC1 genotype and other antioxidants. We used a food-frequency questionnaire to assess lycopene intake in a case-control study of prostate cancer in North Carolina. Plasma α-tocopherol and β-carotene levels were measured using high-performance liquid chromatography. XRCC1 genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. The final dataset included 77 cases and 174 controls with complete questionnaires, genotyping, and plasma analyses. Among men with the Arg/Arg genotype at codon 399, odds ratios (ORs) for prostate cancer risk associated with medium (732–1,529 μg/day) and high (>1,529 μg/day) lycopene intake were 0.59 (95% confidence interval = 0.23–1.50) and 0.21 (0.06–0.71), respectively (Ptrend < 0.01). Similar analyses for persons with Arg/Gln or Gln/Gln genotypes produced null results. Above-median (1,048 μg/day) lycopene intake combined with above-median levels of α-tocopherol and β-carotene was associated with an OR of 0.11 (0.02–0.65) among men with the Arg/Arg genotype but not those with at least one Gln allele (Pinteraction = 0.01). Although limited by small sample size, these findings indicate that the association between lycopene and prostate cancer is complex and may be modified by other antioxidants and by XRCC1 genotype.

The value of pharmacogenomic analysis of microsatellite instability (MSI) and XPD, XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma

13011 Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort. No significant financial relationships to disclose.

Clinical outcome of gemcitabine (gem)/cisplatin (cis)- vs docetaxel (doc)/cis-treated stage IV non-small cell lung cancer (NSCLC) patients (p) according to X-ray repair cross-complementing group 3 (XRCC3) polymorphism and age

7055 Background: Significant interaction between XRCC1 genotype and age has been reported, with younger subjects having a greater risk of developing lung cancer. Carriers of XRCC3 241 MetMet have higher levels of DNA adducts, leading us to hypothesize that they would be more chemosensitive, especially younger patients. Methods: Real-time PCR assay was used to determine XRCC3 genotype from DNA isolated from baseline blood samples of 878 stage IV NSCLC p (162 treated with gem/cis; 716 with doc/cis). Median age, 60; 266 p (30%) &lt;55; 239 p (39%) 55–66; 273 p (31%) &gt;66. Adenocarcinoma: 459 p (53%). Homozygous variant XRCC3 241 MetMet was found in 124 p (14%), with the same frequency in each of the three age groups. Results: After a median follow-up of 7.6 months (m) (95% CI, 1–47 m), overall median survival (MS) was 9.5 m (95% CI, 8.8–10.2 m), with no differences between the 2 regimens. In all p with XRCC3 241 MetMet, MS was 12.9 m for p treated with gem/cis and 8.4 m for p treated with doc/cis (P = 0.06) (hazard ratio at 2 y = 0.23). In p with XRCC3 241 MetMet &lt;55 y, MS was not reached for p treated with gem/cis and 9.2 m for p treated with doc/cis (P = 0.02), which translated into a 60% difference in survival at 2 y. This difference diminished in p with XRCC3 241 MetMet 55–66 y (MS 12.9 m with gem/cis, 6.9 m with doc/cis [P = 0.09]; 28% difference in survival at 2 y) and disappeared in p &gt;66 y (MS 5.8 m with gem/cis, 7.8 m with doc/cis [P = 0.55]. For the other XRCC3 241 genotypes (ThrThr and ThrMet), no differences in MS were found either overall or broken down by age. Conclusions: XRCC3 241 MetMet is both an easily assessable and robust predictive marker for survival in younger gem/cis-treated NSCLC p. The survival benefit dwindles with increasing age, possibly related to the enhanced DNA repair capacity of older p. No significant financial relationships to disclose.

Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk

To date, the potential impact of hormones on prostate cancer has predominantly focused on receptor-mediated events. However, catechol estrogens, if not inactivated by catechol-O-methyltransferase (COMT), can generate large quantities of reactive oxygen species (ROS). ROS may cause a spectrum of damage including oxidative DNA base lesions, which can lead to irreversible mutation(s) if they are not repaired by base excision repair (BER) systems. hOGG1 is a key enzyme in short patch BER because it recognizes and performs initial excision of the most common form of oxidative DNA base damage, 8-hydroxyguanine (8-oxo-dG). To investigate potential non-receptor-mediated estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and prostate cancer in a family-based case-control study (439 prostate cancer cases, 479 brother controls). We observed no noteworthy associations between these polymorphisms and prostate cancer risk in the total study population. However, among men with more aggressive prostate cancer, the hOGG1 326 Cys/Cys genotype was inversely associated with disease (OR=0.30; 95% CI=0.09-0.98). Combining the lower activity CYP1B1 432 Leu/Leu or Leu/Val genotypes (which may decrease the level of catechol estrogens and ROS generated) with the hOGG1 326 Cys/Cys genotype and the XRCC1 399 Arg/Arg or Arg/Gln genotypes (which may enhance BER) resulted in an even further reduced risk in Caucasians with more aggressive disease (OR=0.09; 95% CI=0.01-0.56). Including the high-activity COMT 158Val allele to this combination also lowered aggressive prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88). The decreased risk we observed with the hOGG1 326 Cys/Cys genotype confirms an earlier report and the further reduced risk found with the CYP1B1 (432 Leu/Leu or Leu/Val)-hOGG1 (326 Cys/Cys)-XRCC1 (Arg/Arg or Arg/Gln) genotype combination may lend new insights to the importance of ROS generated from non-receptor-mediated estrogenic mechanisms in more aggressive prostate cancer.

An intronic polymorphism associated with increased XRCC1 expression, reduced apoptosis and familial breast cancer

XRCC1 coordinates the activities of DNA polymerase-beta and DNA ligase for base excision repair of oxidative DNA damage. In addition, there is some evidence that XRCC1 is a negative regulator of apoptosis. Single nucleotide polymorphisms in XRCC1 have been inconsistently associated with breast cancer risk. We evaluated XRCC1 gene expression in breast cancer cell lines and carcinogen-induced apoptosis in benign breast epithelial cells in relation to XRCC1 genotypes. XRCC1 IVS10+141G>A was associated with increased expression of XRCC1 mRNA and protein, and reduced apoptosis in response to benzo-[a]-pyrene or ionizing radiation, but XRCC1 R399Q was not. These genotypes were also assessed in a clinic-based sample that included 190 breast cancer patients with a family history of breast cancer and 95 controls with no family history of breast cancer. Heterozygous XRCC1 IVS10+141G>A was associated with an increased breast cancer risk (O.R. = 1.7, 95% C.I. 1.016-2.827, P = 0.04) as was homozygous XRCC1 IVS10+141G>A (O.R. = 4.7, 95% C.I. 1.028-21.444, P = 0.03). XRCC1 R399Q was not associated with breast cancer (O.R. 1.00, 95% C.I. 0.61-1.64). The XRCC1 IVS10+141G>A locus is centered in a sequence that is nearly identical to the consensus binding site for the PLAG1 transcription factor. XRCC1 IVS10+141G>A is an intronic polymorphism that is associated with XRCC1 expression, apoptosis and familial breast cancer. It may occur within an intronic regulatory sequence.

Relationship between GSTT1, GSTM1, NQO1, RAD51 and XRCC3 genes polymorphisms and chronic myeloid leukemia

目的 探讨GSTT1、GSTM1、NQO1、RAD51和XRCC3基因多态性与我国慢性粒细胞白血病(CML)发生遗传易感之间的关系.方法共120例CML患者和458名与患者无血缘关系的正常人,用多重PCR方法检测GSTT1和GSTM1基因型,用PCR-RFLP方法分析RAD51,XRCC3,NQO1基因型.结果CML患者GSTT1和GSTM1缺失型比例分别为50.8%和59.2%,与正常对照组无显著差异(分别为42.8%和53.1%).CML患者NQO1 C/T和T/T基因型的比例(60.0%)、RAD51 G135CG/C基因型比例(26.9%)和XRCC3-241Met杂合子缺失型(Thr/Met)的比例(9.2%)均与正常对照组(分别为65.3%,12.4%和9.2%)无统计学差异.结论本研究结果提示GSTT1、GSTM1、NQO1、RAD51和XRCC3基因型与我国CML的发生无显著相关性。

Dose-dependent influence of genetic polymorphisms on DNA damage induced by styrene oxide, ethylene oxide and gamma-radiation

Styrene oxide (SO), ethylene oxide (EO) and gamma-radiation (G) are agents with a well-described metabolism and genotoxicity. EPHX1 and GSTs play an important role in the detoxification of electrophiles and oxidative stress. Enzymes involved in base excision repair (hOGG1, XRCC1), in rejoining single strand breaks (XRCC1) and in repair of cross-links and chromosomal double strand breaks (XRCC3) might have an impact on genotoxicity as well. In this study we assessed the dose-dependent effect of genetic polymorphisms in biotransforming ( EPHX (Tyr 113/His 113 and His 139/Arg 139), GSTP1 (Ile 105/Val 105), GSTM1 and GSTT1) and DNA repair enzymes ( hOGG1 (Ser 326/Cys 326), XRCC1 (Arg 194/Trp 194, Arg 280/His 280, Arg 399/Gln 399), XRCC3 (Thr 241/Met 241)) on the induced genotoxicity. Peripheral blood mononuclear cells from 20 individuals were exposed to 3 doses per agent (+control). Genotoxicity was evaluated by measuring comet tail length (TL) and micronucleus frequencies in binucleated cells (MNCB). Dose-dependent DNA damage was found for all agents and end-points, with the exception of MNCB induced by EO. Repeated measure ANOVA revealed a significant contribution of hOGG1 and XRCC3 genotypes to the inter-individual variability of TL and MNCB in cells exposed to EO and G. Homozygous hOGG1 326 wild cells showed significantly lower EO-induced TL than the heterozygous cells. Significantly higher TL and MNCB were found in EO-exposed cells carrying the XRCC3 241Met variant and the influence on TL was more pronounced at higher dose. In G-irradiated cells, TL was significantly higher in the hOGG1 326 homozygous wild types compared with mutated genotypes. The influence of hOGG1 326 on TL was borderline dose-dependent. We conclude that the influence of genetic polymorphisms of enzymes involved in DNA repair on induced genotoxicity depends on exposure dose.

Association of genetic polymorphism in DNA repair gene XRCC1 with risk of lung adenocarcinoma in nonsmoking women

XRCC1 polymorphism at Arg399Gln site has been shown to modulate DNA repair capacity. The aim of this study is to assess the relationship between XRCC1 polymorphism and susceptibility to lung adenocarcinoma in nonsmoking female via a hospital-based case-control study. Cases were 126 female patients with lung adenocarcinoma from January 2002 to October 2004 in China Medical University Hospital and Liaoning Tumor Hospital. Controls were selected from patients with other pulmonary diseases in the hospitals at the same time. These controls were matched to cases on age (±5 years). Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. XRCC1 genotypes were determined by PCR-RFLP. The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Cases showed a higher prevalence of oil smoke compared with controls (P < 0.05). The frequencies of Arg/Arg, Arg/Gln and Gln/Gln in lung adenocarcinoma group (32.54%, 42.86%, 24.60%) were significantly different from those in controls (54.76%, 40.48%, 4.76%) (P < 0.05). The individual carrying Gln/Gln genotype was at a significantly increased risk of lung adenocarcinoma compared with those with Arg/Arg genotype (OR=8.695, 95%CI 3.343-22.614, adjusted for age and oil smoke exposure). Furthermore, the OR of lung adenocarcinoma for the variant XRCC1 399Gln allele combined with exposure to oil smoke was 5.21 (95%CI 1.85-14.70, P < 0.001). The results indicate that the Arg399Gln polymorphism in XRCC1 is associated with the risk of lung adenocarcinoma in nonsmoking women.

Association of metabolic and DNA repair enzyme gene polymorphisms and DNA damage in coke-oven workers

To investigate the association of polymorphisms of metabolic and DNA repair enzyme genes and DNA damage in peripheral blood lymphocytes in coke-oven workers. One hundred and forty-four coke-oven workers and 50 controls were recruited in this study. Urinary 1-hydroxypyrene (1-OHP) levels were measured as the internal dose of polycyclic aromatic hydrocarbons exposure. DNA damage was detected by alkaline comet assay, and the value of 1.74 was used as the cut-off value to determine whether the individual's DNA damage was positive. The genotypes of CYP1A1, CYP2E1, GSTP1, NQO1, mEH and XRCC1 were determined by PCR-based methods. With adjustment for urinary 1-OHP, age, sex, multiple analysis of covariance was used to study the association between genotypes and the ln-transformed olive TM and multiple logistic regression was used to calculate the adjusted OR and the 95% CI for the risk of DNA damage. In 144 coke-oven workers, with adjustment for urinary 1-OHP, coking history and sex, the olive TM was significantly higher with XRCC1 280His allele than those with Arg allele (5.6 vs. 2.8, P < 0.01). The subjects with XRCC1 280His allele also have significantly higher risk for DNA damage than subjects with Arg allele (adjusted OR = 2.66, 95% CI = 1.00-7.14, P = 0.05) and the subjects with GSTP1 104Val allele have higher risk for DNA damage than subjects with Ile allele (adjusted OR = 1.90, 95% CI = 0.94-3.85, P = 0.07). XRCC1 and GSTP1 polymorphisms might influence the susceptibility of DNA damage in occupational PAH-exposed coke-oven workers.