XRCC1 Polymorphisms Research Articles

DNA Repair Gene XRCC1 and XPD Polymorphisms and Gastric Cancer Risk: A Case-Control Study Outcome from Kashmir, India.

Coding polymorphisms in several DNA repair genes have been reported to affect the DNA repair capacity and are associated with genetic susceptibility to many human cancers, including gastric cancer. An understanding of these DNA repair gene polymorphisms might assess not only the risk of humans exposed to environmental carcinogens but also their responses to different therapeutical approaches, which target the DNA repair pathway. In the present study, polymorphic variants of two DNA repair genes, XRCC1 Arg399Gln and XPD Lys751Gln, were chosen to be studied in association with gastric cancer susceptibility in the Kashmiri population. A total of 180 confirmed cases of gastric cancer (GC) and 200 hospital-based controls from Government Shri Maharaja Hari Singh Hospital, Srinagar, were included in the study. The genotyping for XRCC1 and XPD genes was carried out by polymerase chain reaction-restriction fragment length polymorphism. We found that tobacco smoking is strongly associated with GC risk (OR = 25.65; 95% CI: 5.49–119.7). However, we did not find any association of polymorphism of XRCC1 Arg399Gln (OR = 1.56; 95% CI: 0.32–7.82) and XPD Lys751Gln (OR = 0.46; CI: 0.10–2.19) with GC risk in the study population. The combination of genotypes and gender stratification of XRCC1 and XPD genotypic frequency did not change the results. Consumption of large volumes of salt tea was also not associated with gastric cancer risk. Polymorphic variants of XRCC1 Arg399Gln and XPD Lys751Gln are not associated with the risk of gastric cancer in the Kashmiri population. However, replicative studies with larger sample size are needed to substantiate the findings.

Polymorphism of XRCC1 Gene Exon 6 (Arg194Trp) in Relation to Micronucleus Frequencies in Hospital Radiation Workers

The genetic polymorphism of DNA repair gene play s some important role in regulating individual sensitivity to ionizing radiation , maintaining DNA integrity , and prevent ing cance r and DNA damage . X RCC 1 as one of the members of base excision repair ( BER ) is involved in the repair ement of oxidized bases and single-strand breaks DNA after exposure by ROS , including ionizing radiation. This study was aimed to examine the correlation between XRCC1 exon 6 gene polymorphism and MN frequency in radiation workers and their relation to age, gender, smoking status and years of exposure. This study involved 81 hospital radiation workers and 20 controls from several hospitals in Indonesia . Genotyping of XRCC1 exon 6 gene polymorphism and MN assay were performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Cytokinesis-Block Micronucleus assay (CBMN assay), respectively. The results indicated that MN frequency was significantly higher in the exposed workers than in the controls ( 15. 38 ±7. 72 versus 9±5. 49 ; p = 0.001). Radiation workers with heterozygous alleles for XRCC1 polymorphisms showed a significantly higher MN frequency than controls with the same genotypes ( 17. 5 ±8. 36 versus 7. 44 ±5. 05 ; p = 0.002). The confounding factors, like gender and age, were significantly associated with increased MN frequency both in radiation workers and controls. Smoking status was significantly associated with MN frequency in the controls only, while years of exposure did not affect MN frequency either in radiation workers or controls. These results suggest that the genetic polymorphism of XRCC1 gene exon 6 with a mutant heterozygous/ CT variant demonstrated an association with the extent of DNA damage in the hospital radiation workers in this study. In the subsequent studies, it is necessary to examine the DNA repair genes polymorphism in populations with controlled non-genetic factors, such as lifestyles, environments, and exercises that affect the MN frequency as a biomarker of DNA damage.

Clinicopathological significance of SNPs in RAD51 and XRCC3 in oral and oropharyngeal carcinomas.

This study investigated the influence of single nucleotide polymorphisms (SNP) in RAD51 and XRCC3 on susceptibility to oral and oropharyngeal squamous cell carcinomas (SCC) and determined their clinicopathological significance. SNPs rs1801320 and rs1801321 in RAD51 and rs861539 in XRCC3 were genotyped in 81 patients presenting oral SCC, 45 presenting oropharyngeal SCC, and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as gene-gene (GxG) interaction and gene-environmental factor (GxE) interaction. Clinicopathological associations were verified through the chi-square test, and univariate and multivariate methods were applied for survival analyses. Although allelic and genotypic models and the GxG interaction analysis were nonsignificant, the GxE analysis revealed synergistic effects of the risk alleles of rs1801320, rs1801321, and rs861539 with smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC. Furthermore, oropharyngeal SCC patients carrying the XRCC3 rs861539 GT/TT genotype (T risk allele) presented a shorter overall survival than GG genotype carriers. Combined effects of RAD51 (rs1801320 and rs1801321) and XRCC3 (rs861539) SNPs with environmental carcinogens (tobacco and alcohol) are associated with oral and oropharyngeal SCC development.

Association of Genetic Variations in XRCC1 and ERCC1 Genes with Sporadic Breast Cancer

Background: Recently, findings have validated the significant role of DNA damage genes related to the pathogenesis of breast cancer (BC). The aim of the present investigation was to evaluate possibility roles of two common XRCC1 (rs25487; A > G) and ERCC1 (rs3212964; A > G) gene polymorphisms with the risk of sporadic BC. Methods: In a case-control study, consisting of 100 females identified with sporadic BC and 100 malignancy-free females as the control group. We used Tetra-ARMS Polymerase Chain Reaction (PCR) and PCR-Restriction Fragment Length Polymorphism (RFLP) methods to determine genotype frequencies of XRCC1 and ERCC1 genes. Results: The findings did not reveal a statistically significant difference in the genotype frequencies of XRCC1 and ERCC1 genes between the two groups (P > 0.05). The frequency of G mutant allele for XRCC1 and ERCC genes was higher in cases compared to controls, while the difference between the groups was not statistically significant (P = 0.202; OR: 1.312; CI: 0864 - 1.994), (P = 0.352; OR: 1.213; CI: 0.808 - 1.820). Conclusions: The current results provide evidence against the hypothesis that XRCC1 (rs25487) and ERCC1 (rs3212964) gene polymorphisms may be associated with a predisposition to sporadic BC.

Polymorphisms of XRCC1 AND XRCC3 Repair Genes and the Risk of Gastric Cancer in the Amazon Region –Brazil

Polymorphisms of XRCC1 AND XRCC3 Repair Genes and the Risk of Gastric Cancer in the Amazon Region –Brazil

Micronucleus Frequencies and DNA Repair Gene XRCC3 Polymorphism in Radiation Workers of Center for Multipurpose Reactor

The carcinogenic effects of low radiation doses have not been fully understood until now. Studies on individuals that are occupationally exposed to low radiation doses can help to address this question. This study assesses the micronucleus (MN) frequencies as indicator of DNA damage in radiation workers that are occupationally exposed to low radiation dose. The influence of single nucleotide polymorphisms (SNPs) in XRCC3 gene on the frequency of micronuclei was also evaluated in this study. The effects of confounding factors of gender, age, and smoking status on MN frequencies was assessed in all samples. A total of 60 subjects consisting of 30 radiation workers from Center of Multipurpose Reactor (CMPR), National Nuclear Energy Agency (NNEA) of Indonesia, and 30 control samples were enrolled in this study. The results showed that the difference between MN frequency in radiation workers and in control samples was not statistically significant [0.019 vs. 0.021; p = 0.549]. Age and smoking status did not affect micronucleus frequencies in all samples ( p = 0.723 and 0.828). Micronucleus frequencies in females were higher compared to males, even though the difference was not significant ( p = 0.3). Radiation workers with variant alleles for XRCC3 olymorphism did not showed higher MN frequencies compared to the controls with the same genotypes. The small numbers of samples with XRCC3 variant alleles found in this study possibly contributed to the insignificant difference of MN frequencies between wild-type allele ( Thr/Thr ) and mutant alleles ( Thr/Met or Met/Met ). Further investigations using larger sample sizes and MN assay in combination with human pan-centromeric probe should be conducted to validate this study results. Other SNP in XRCC3 gene also should be evaluated to find out the association between SNP and MN frequencies.

Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients.

Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI95% = 1.12-5.69) and XRCC1 rs25487-GG (p = 0.0161; OR = 2.99; CI95% = 1.26-7.62) genotype showed significantly better ORR. Cox survival analysis revealed that patients carrying the MDM2 rs1690924-GG genotype (p = 0.0345; HR = 1.99; CI95% = 1.05-3.80) presented higher risk of death. Furthermore, carriers of MTR rs1805087-A alleles (p = 0.0060; HR = 8.91; CI95% = 1.87-42.42) and SLC19A1 rs1051266-AA genotype (p = 0.0130; HR = 1.74; CI95% = 1.12-2.68) showed greater risk of progression. No influence of ERCC1 rs11615, ERCC2 rs13181, ERCC2 rs1799793, XRCC1 rs1799782, MDM2 rs1470383, MTHFR rs1801131, and MTHFR rs1801133 on platinum-based chemotherapy clinical outcomes was found. In conclusion, our results suggest that ERCC1 rs3212986, XRCC1 rs25487, MDM2 rs1690924, MTR rs1805087, and SLC19A1 rs1051266 gene polymorphisms may significantly act as predictive factors in NSCLC patients treated with platinum-based chemotherapy.

Base excision repair (OGG1 and XRCC1) and metabolism (PON1) gene polymorphisms act on modulation of DNA damage and immune parameters in tobacco farmers

Pesticides are one of the most frequently investigated chemical, due to their multiple uses in agricultural and public health areas. This study evaluates lymphocytes CBMN (cytokinesis-block micronucleus cytome assay), inflammatory markers, inorganic elements in blood samples, and the relationship of these parameters with XRCC1Arg194Trp, OGG1Ser326Cys and PON1Gln192Arg polymorphisms in a population of tobacco farmers. The study population comprised 129 agricultural workers exposed to pesticides and 91 nonexposed. Farmers had significantly increased NPB (nuclear plasmatic bridge), MN (micronucleus) and NBUD (nuclear bud) frequencies, as well as IL-6 (interleukin 6) and TNF-α (tumor necrosis factor alpha) serum levels, and decreased cytokines CD4+/CD8+ ratio. In the exposed group, XRCC1 Trp/- was correlated with decreased NDI (nuclear division index), and OGG1 Cys/- was associated with higher levels of NPB and decreased levels of IL-6. The combined effects of PON1 Arg/- and XRCC1 Arg/Arg were associated with increased NPB frequencies. In addition, the combination of PON1 Arg/- with XRCC1 Trp/- or OGG1 Cys/- influenced in increased levels of necrosis in farmers. Furthermore, tobacco farmers showed a positive correlation between TNF-α levels and NPB, CD4+/CD8+ ratio and NBUD; and IL-6 levels with both MN and NDI. The duration of years of work at tobacco fields was correlated positively with NBUD frequency. Sulfur, chlorine and potassium were found at increased levels in the exposed group when compared to the nonexposed one. These findings provide evidence that tobacco farmers’ exposure have increased DNA damage and alter the immune system’s response, and that XRCC1 and OGG1 polymorphisms could influence both biomarkers results.

PO-1098: Association of XRCC1 polymorphism with laryngeal SCC & with treatment response to chemoradiation

PO-1098: Association of XRCC1 polymorphism with laryngeal SCC & with treatment response to chemoradiation

CASP8, XRCC1, WRN, NF2, and BRIP1 Polymorphisms Analysis Shows Their Genetic Susceptibility for Meningioma Risk and the Association with Tumor-Related Phenotype in a Chinese Population.

To investigate 10 candidate single nucleotide polymorphisms (SNPs) in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk in a Chinese population. We examined 10 candidate SNPs in 5 genes (CASP8, XRCC1, WRN, NF2, and BRIP1) to confirm the association between the 5 genes and the meningioma risk and tumor-related phenotype in 433 individuals, including 215 patients with meningioma and 218 controls. The polymorphisms rs4968451T>G in BRIP1 were significantly associated with the risk of meningioma (TT vs. TG vs. GG additive, P= 0.005; TT+TG vs. GG dominant, P= 0.015; TT/GT+GG recessive, P= 0.034). The significant association was found only in females for BRIP1 rs4968451T>G (TT+TG vs. GG dominant, P= 0.001; TT/GT+GG recessive, P= 0.044). We observed no significant association between genotypes and the meningioma risk for the other 9 SNPs. Through genotype-phenotype analysis, the genotype of BRIP1 rs4968451T>G was also strongly associated with tumor-related phenotypes, including the tumor grade and tumor subtypes. BRIP1 rs4968451T>G was associated with markedly grade I meningioma risk (TT+TG vs. GG dominant, P= 0.008; TT/GT+GG recessive, P= 0.020). In addition, BRIP1 rs4968451T>G was associated with markedly meningothelial and transitional meningioma risk. Furthermore, the genotype of CAPS8, XRCC1, and NF2 was associated with different subtype of meningioma risk. This study indicated a role for BRIP1 gene variations in meningioma and may be informative for future genetic or biological studies of meningioma. These findings will assist in further understanding the genetic cause for meningiomas and guide more effective biological interventions to facilitate meningiomas.

Combined effect of ERCC1 and ERCC2 polymorphisms on overall survival in non-squamous non-small-cell lung cancer patients treated with first-line pemetrexed/platinum

ObjectivesPolymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy. Materials and methodsGenotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays. ResultsThe wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001). ConclusionA combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.

GSTP1 Ile105Val polymorphism might be associated with the risk of radiation pneumonitis among lung cancer patients in Chinese population: A prospective study.

Background: Growing data suggest that DNA damage repair and detoxification pathways play crucial roles in radiation-induced toxicities. To determine whether common functional single-nucleotide polymorphisms (SNPs) in candidate genes from these pathways can be used as predictors of radiation pneumonitis (RP), we conducted a prospective study to evaluate the associations between functional SNPs and risk of RP.Methods: We recruited a total of 149 lung cancer patients who had received intensity modulated radiation therapy (IMRT). GSTP1 and XRCC1 were genotyped using the SurPlexTM-xTAG method in all patients. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Kaplan-Meier analysis was used to determine the cumulative probability of RP of grade ≥ 2. Cox proportional hazard regression was performed to identify clinical variables and SNPs associated with risk of RP grade ≥ 2, using univariate and multivariate analysis, respectively.Results: With a median follow-up of 9 months, the incidence of RP of grade ≥ 2 was 38.3%. A predicting role in RP was observed for the GSTP1 SNP (adjusted hazard ratio 3.543; 95% CI 1.770-7.092; adjusted P< 0.001 for the Ile/Val and Val/Val genotypes versus Ile/Ile genotype). Whereas, we found that patients with XRCC1 399Arg/Gln and Gln/Gln genotypes had a lower risk of RP compares with those carrying Arg/Arg genotype (adjusted HR 0.653; 95% CI 0.342-1.245), but with no statistical significance observed (adjusted P = 0.195).Conclusions: Our results suggested a novel association between GSTP1 SNP 105Ile/Val and risk of RP development, which suggests the potential use of this genetic polymorphism as a predictor of RP. In addition, genetic polymorphisms of XRCC1 399Arg/Gln may also be associated with RP.

Single Nucleotide Polymorphisms of XRCC1 and the Risk of Head and Neck Cancer

Single Nucleotide Polymorphisms of XRCC1 and the Risk of Head and Neck Cancer

Potential Role of Single Nucleotide Polymorphisms of XRCC1, XRCC3, and RAD51 in Predicting Acute Toxicity in Rectal Cancer Patients Treated With Preoperative Radiochemotherapy.

To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. The observed grade ≥3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy).RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade ≥3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade ≥3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy.

Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer

Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC.No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

Genetic variants of SULT1A1 and XRCC1 genes and risk of lung cancer in Bangladeshi population.

Lung cancer is one of the most frequently occurring cancers throughout the world as well as in Bangladesh. This study aimed to correlate the prognostic and/or predictive value of functional polymorphisms in SULT1A1 (rs9282861) and XRCC1 (rs25487) genes and lung cancer risk in Bangladeshi population. A case-control study was conducted which comprises 202 lung cancer patients and 242 healthy volunteers taking into account the age, sex, and smoking status. After isolation of genomic DNA, genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method and the lung cancer risk was evaluated as odds ratio that was adjusted for age, sex, and smoking status. A significant association was found between SULT1A1 rs9282861 and XRCC1 rs25487 polymorphisms and lung cancer risk. In case of rs9282861 polymorphism, Arg/His (adjusted odds ratio = 5.06, 95% confidence interval = 3.05-8.41, p < 0.05) and His/His (adjusted odds ratio = 3.88, 95% confidence interval = 2.20-6.82, p < 0.05) genotypes were strongly associated with increased risk of lung cancer in comparison to the Arg/Arg genotype. In case of rs25487 polymorphism, Arg/Gln heterozygote (adjusted odds ratio = 4.57, 95% confidence interval = 2.79-7.46, p < 0.05) and Gln/Gln mutant homozygote (adjusted odds ratio = 4.99, 95% confidence interval = 2.66-9.36, p < 0.05) were also found to be significantly associated with increased risk of lung cancer. This study demonstrates that the presence of His allele and Gln allele in case of SULT1A1 rs9282861 and XRCC1 rs25487, respectively, involve in lung cancer prognosis in Bangladeshi population.

Genetic Variations of DNA Repair Genes in Breast Cancer.

Genetic variations in DNA repair genes may affect DNA repair capacity therefore increase risk for cancer. In our study, we evaluted the relation between DNA repair gene polymorphisms XRCC1 rs1799782, rs25487, rs25489; XPC rs2228000, rs2228001; XPD rs1799793, rs13181; XRCC3 rs861539; RAD51B rs10483813, rs1314913 and breast cancer risk for 202 Turkish cases in total, in which 102 patients with breast cancer and 100 controls. Genotyping of the DNA samples was carried out by multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) using Sequenom MassARRAY 4 analyzer. Genotype and allele distributions were calculated between the groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. rs25487 AA genotype and A allele was found to be increased in the control group (respectively, OR 0.16 95% CI 0.02-1.06, p=0.058; OR 1.55, 95% CI 1.01-2.36, p=0.043) and rs861539 T allele was found to be decreased in the patient group (OR 1.53, 95% CI 1.01-2.30, p=0.049). No association with breast cancer was found for the remaining SNPs. Our findings suggest that XRCC1 rs25487 AA genotype and A allele, XRCC3 rs861539 T allele may have protective effects in breast cancer for Turkish population.

Occupational radiation exposure and genetic polymorphisms in DNA repair genes

Radiation sensitivity appears to be influenced by genetic polymorphisms in some DNA repair genes and individuals with low DNA repair capacity can be at increased risk of developing cancer. The aim of the present study was to determine the impact of gene polymorphisms on DNA damages in the form of micronuclei (MN) in circulating lymphocytes of interventional cardiologists (ICs), occupationally exposed to ionizing radiation. MN frequency was significantly higher in the ICs than in the controls (27.7 ± 17.2‰ vs. 8.0 ± 2.6‰, p < 0.0005). MN values were higher in the ICs with exposure of ≥ 10 years and ≥ 3 mSv in comparison to the related referents. The analysis of different interactions showed significantly higher MN frequencies in ICs exposed to ≥ 10 mSv carrying the variant-type XRCC3 241Met genotype compared to those of wild-type XRCC3 (Thr/Thr) genotype. In the ICs carrying both wild-type alleles for XRCC3 and MSH3 polymorphisms showed a significantly lower MN frequency compared to the exposed individuals with one or two variant alleles for XRCC3 and MSH3 polymorphisms. In conclusion, ICs showed significantly higher MN frequencies than in the control, and this effect was higher in individuals carrying the variant-type XRCC3 241Met genotype. These results not only show the need for improvement of safety and training programs for ICs but also may be helpful in developing amenable screening tests for identifying radiosensitive workers and applying suitable radiation protection job-specific strategies for effective dose reduction.

Correlations between microsatellite instability, ERCC1/XRCC1 polymorphism and clinical characteristics, and FOLFOX adjuvant chemotherapy effect of colorectal cancer patients

Patients with MSI colorectal tumor have good prognosis and cannot benefit from 5-fluorouracil (5-Fu)-based chemotherapy reported by previous studies. While, single nucleotide polymorphisms (SNP) of ERCC1 and XRCC1 have be proved to influence clinical outcome of colorectal cancer patients treated with oxaliplatin-based chemotherapy. We aim to study the correlation between molecular status and clinical- pathological features, and their effect on CRC patients' clinical outcome treated with mFOLFOX6 adjuvant chemotherapy. In this study, MSI status was determined in tumors and paired normal tissues from 101 colorectal cancer (CRC) patients. We also examined SNP of ERCC1 (c. C354T) and XRCC1 (c.G1196A) in 83 and 85 patients' blood. MSI was found to be significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). CEA and CA19-9 levels was positive correlated significantly by Spearman correlation analysis (Pearson's r = 0.823, p < 0.0001). No significant correlation was found between MSI status and ERCC1/XRCC1 polymorphisms. We found greater drop of CEA level in mFOLFOX6 sensitive group than low sensitive group after mFOLFOX6 adjuvant chemotherapy according to MSI status, ERCC1 and XRCC1 SNP. MSI was significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). The MSI status, ERCC1 and XRCC1 polymorphisms may influence the clinical outcome of colorectal cancer patients treated with mFOLFOX6 adjuvant chemotherapy.

Polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes, CYP1A1 xenobiotic metabolism gene, and tobacco are associated with bladder cancer susceptibility in Tunisian population

Other than the established environmental risk factors associated with bladder cancer (BC), little is known about the genetic variations determining the individual susceptibility of this complex disease. This study aimed to investigate the relationship of BC with environmental agents and polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes and CYP1A1, CYP2D6, NAT1, and NAT2 xenobiotic metabolism genes through a hospital-based case-control study in Tunisia. The selection of the single nucleotide polymorphisms (SNPs) (rs25487, rs 13181, rs415407, rs446421, rs1058172, rs4921880, and rs1208) was performed using the dbSNP database. DNA genotyping was determined by PCR-RFLP after DNA extraction from whole blood. The risks of BC associated with every polymorphism as well as the studied environmental factors were estimated by multivariate-adjusted logistic regression using R software. In addition, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results showed that tobacco smoking and chewing parameters were significantly associated with BC risk. Single-gene variant analysis showed significant associations of the TT genotype of CYP1A1 and the rare GG genotype of ERCC2 with bladder cancer susceptibility (OR=1.34, 95% CI 1.22-1.40, P<0.0001). According to GMDR analysis, our findings indicated a significant association between BC and gene-gene interaction among the CYP1A1, ERCC3, and XRCC1. The present results suggest a potential role of XRCC1, ERCC2, ERCC3, and CYP1A1 besides tobacco intake in susceptibility to BC.