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Aims: Oxaliplatin-based chemotherapy for colorectal cancer demonstrates interindividual variability in response, and polymorphisms of ERCC1, ERCC2, XRCC1, GSTP1 and GSTM1 genes may be contributing factors. Additionally, the effect of these genotypes may differ between ethnic groups. Material & Methods: A meta-analysis of the association between these genotypes and response, progression-free survival and overall survival (OS) for patients with colorectal cancer treated with oxaliplatin-based therapy is reported. Results: ERCC1 C118T (TT vs CC OS [hazard ratio (HR): 2.59; p = 0.001]), ERCC2 A2251C (CC or AC vs AA OS [HR: 1.53; p = 0.04]) and GSTP1 A313G (GG vs AA OS, [HR: 0.47; p < 0.001]) polymorphisms were associated with survival. The effect size may be larger for ERCC1 C118T and XRCC1 G1196A in Asian compared with Caucasian populations. No association was apparent for the GSTM1 genotype., Conclusion: ERCC1 C118T, ERCC2 A2251C and GSTP1 A313G polymorphisms were associated with clinical outcomes.

In this study, we examined the role of the miRNA miR-770-5p in cisplatin chemotherapy resistance in ovarian cancer (OVC) patients. miR-770-5p expression was reduced in platinum-resistant patients. Using a 6.128-fold in expression as the cutoff value, miR-770-5p expression served as a prognostic biomarker and predicted the response to cisplatin treatment and survival among OVC patients. Overexpression of miR-770-5p in vitro reduced survival in chemoresistant cell lines after cisplatin treatment. ERCC2, a target gene of miR-770-5p that participates in the NER system, was negatively regulated by miR-770-5p. siRNA-mediated silencing of ERCC2 reversed the inhibition of apoptosis resulting from miR-770-5p downreglation in A2780S cells. A comet assay confirmed that this restoration of cisplatin chemosensitivity was due to the inhibition of DNA repair. These findings suggest that endogenous miR-770-5p may function as an anti-oncogene and promote chemosensitivity in OVC, at least in part by downregulating ERCC2. miR-770-5p may therefore be a useful biomarker for predicting chemosensitivity to cisplatin in OVC patients and improve the selection of effective, more personalized, treatment strategies., Competing Interests: The authors have no potential conflicts of interest to disclose.

Within DNA repair genes, there lie a number of single nucleotide polymorphisms that may impair protein function and attenuate DNA repair capability, resulting in genomic instability and individual predisposition to malignancies. The purpose of this study was to assess the previously reported inconsistent association of polymorphisms in ERCC1 (rs11615, rs3212986), ERCC2 (rs13181, rs1799793, rs238406), and ERCC5 (rs17655) with the development of brain tumors. In the present work, we carried out a comprehensive meta-analysis of results from all published data (5 data sets for rs11615, 7 for rs3212986, 11 for rs13181, 5 for rs1799793, 3 for rs238406, and 4 for rs17655) to evaluate risk of brain tumors contributed by the polymorphisms being investigated. Either the analytic method described by Mantel and Haenszel or that proposed by DerSimonian and Laird was properly used to summarize the risk estimates (OR and 95% CI). Data analyses were done with Stata version 12.0. Meta-analyses were performed for all polymorphisms, and only rs3212986 in the ERCC1 gene showed a significant association with glioma incidence. In the homozygote comparison, we found 1.26-fold elevated risk of glioma in relation to presence of the AA genotype (OR = 1.26, 95% CI = 1.05-1.52, P OR = 0.013, P heterogeneity = 0.849, I(2) = 0.0%). We also noted that individuals with the rs3212986-AA as compared to those with rs3212986-CC/CA had a 28% higher risk to develop glioma (OR = 1.28, 95% CI = 1.06-1.53, P OR = 0.008, Pheterogeneity = 0.808, I(2) = 0.0%). No major effects were observed for Caucasians or Asians in subgroup analysis by ethnicity. ERCC1 rs3212986 is a common single nucleotide polymorphism and may contribute toward individual susceptibility for glioma. Further research in this filed is required to verify the association obtained based on a relatively small number.

Several new chemotherapeutic agents have become available for the treatment of colorectal cancer, which has led to increased complexity in treatment planning. Treatment decision making for individual patients could be facilitated if guided by predictive and prognostic markers. As most cytotoxic drugs induce DNA damage, the DNA damage repair pathways hold potential for yielding such biomarkers. Here, we review the current evidence of a possible involvement of the nucleotide excision repair pathway in the efficacy of chemotherapeutic agents used in the treatment of colorectal cancer. Although a large number of studies have been conducted, they are generally of moderate size and heterogeneous in design. Up to date no firm conclusions can be drawn to translate these results into the clinic. We recommend further comprehensive investigations of the nucleotide excision repair pathway in large patient studies that include both discovery and validation cohorts.

Background: Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS)., Methods: Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies)., Results: We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes., Conclusions: Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.

Unlabelled: A pathologic complete response to neoadjuvant chemotherapy (NAC) containing platinum is a strong prognostic determinant for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive molecular characterization of bladder cancer, associations of molecular alterations with treatment response are still largely unknown. We selected pathologic complete responders (ypT0N0; n=38) and nonresponders (higher than ypT2; n=33) from a cohort of high-grade MIBC patients treated with NAC. DNA was isolated from prechemotherapy tumor tissue and used for next-generation sequencing of 178 cancer-associated genes (discovery cohort) or targeted sequencing (validation cohort). We found that 9 of 38 complete responders had erb-b2 receptor tyrosine kinase 2 (ERBB2) missense mutations, whereas none of 33 nonresponders had ERBB2 mutations (p=0.003). ERBB2 missense mutations in complete responders were mostly confirmed activating mutations. ERCC2 missense mutations, recently found associated with response to NAC, were more common in complete responders; however, this association did not reach statistical significance in our cohort. We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC., Patient Summary: In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy (NAC) in bladder cancer. We found that mutations in the gene ERBB2 are exclusively present in patients responding to NAC., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Endometrial carcinoma (EC) is the most frequent malignant neoplasm of female genitals and the fourth most frequent malignant neoplasm in Polish women, after breast, colorectal and lung cancer. Despite intensive research, EC aetiology remains unknown. The variability, perceived in DNA repair genes, may be of clinical importance for evaluation of the risk of occurrence of a given type of cancer, its prophylactics and therapy. The aim of the study was to determine the relationship between gene polymorphism R156R (C to A, rs238406) of ERCC2 gene and modulation of the risk of endometrial cancer in Poland. Our research included 1360 patients with EC and 1320 healthy controls. The genotype analysis of ERCC2 gene polymorphism was performed using the PCR-based restriction fragment length polymorphism (PCR-RFLP). In the presented study, a relationship was identified between R156R polymorphism of the ERCC2 gene and the incidence of endometrial cancer. An association was observed between EC occurrence and the presence of A/A genotype (odds ratio (OR) 9.71, 95 % Cl 7.53-12.50, p < .0001). A tendency for an increased risk of endometrial cancer was detected with the occurrence of A allele of ERCC2 polymorphism (OR = 5.95, 95 % Cl 5.23-6.78, p < .0001). A relationship was confirmed between R156R polymorphism and endometrial cancer progression, assessed by histological grades. On the basis of these results, we conclude that ERCC2 gene polymorphism R156R may be associated with an increased risk of endometrial cancer.

Background/aim: Coronary artery disease (CAD) is a chronic inflammatory disease seen as formation of atherosclerotic plaques (atheroma) in coronary arteries. Recent published papers show that DNA damage and repair mechanisms play a crucial role on the development and severity of atheromas. In this study, we investigated nucleotide excision repair (NER) pathway-related gene polymorphisms in atherosclerosis. XPD, encoded by ERCC2 gene, is an ATP-depended helicase enzyme involved in the NER pathway. Ribonucleotide reductase (RR) is a tetra meric enzyme, synthesizing deoxyribonucleotides from ribonucleotides for DNA synthesis. RR is encoded by the RRM1 and RRM2 genes, which are two subunits of RR enzyme., Materials and Methods: DNA samples isolated from peripheral blood were genotyped with real-time polymerase chain reaction (RT-PCR) for RRM1 (rs12806698), RRM2(rs6859180) and ERCC2 (rs13181) genes., Results: The frequency of the RRM1 AC heterozygote genotype was found to be significantly lower (odds ratio (OR)=0.369, 95% confidence interval (CI)=0.179-0.760; p=0.006), whereas the CC homozygote genotype was found to be significantly higher in patients compared to controls (OR=7.636, 95% CI=2.747-21.229; p=0.000). In addition, the RRM1 A allele was higher in control group (p=0.000, OR=0.131 95%CI=0.047-0.364). For the ERCC2 gene, GG genotype was significantly higher in control group (p=0.017, OR=0.387, 95%CI=0.175-0.152) and TT genotype (p=0.021) was higher in CAD group. TT genotype had a ~3-fold increased risk (OR=3.615, 95%CI=1.148-11.380) for CAD. Carrying T allele appears to be a risk factor for CAD (p=0.017, OR=2.586, 95%CI=1.173-5.699), while the G allele might be a risk-reducing factor (p=0.021, OR=0.277, 95%CI=0.088-0.871) for CAD., Conclusion: RRM1 and ERCC gene polymorphisms, having homozygous mutant genotype, might be a risk factor for CAD. RRM1 and ERCC wild type alleles are risk-reducing factor for CAD. Also, carrying RRM1 A allele might have a protective effect for smokers., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

We conducted a prospective study to analyze whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. A total of 228 patients with pathologically proven gastric cancer and receiving platinum-based chemotherapy were recruited from our hospital between October 2009 and October 2011. The ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 polymorphisms were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Conditional logistic regression analysis revealed that patients carrying the CA and AA genotypes of ERCC1 rs3212986 polymorphism showed a poorer response to chemotherapy compared to the CC genotype (CA vs. CC: OR = 0.28, 95% CI = 0.06-0.98, P = 0.04; AA vs. CC: OR = 0.49, 95% CI = 0.06-0.98, P = 0.01). Moreover, the CA+AA genotype of ERCC1 rs3212986 polymorphism showed a significantly poorer response to chemotherapy (CA+AA vs. CC: OR = 0.49, 95% CI = 0.27-0.90). Patients with the AA genotype of ERCC1 rs3212986 polymorphism had a longer overall survival time when compared with the CC genotype (34.91 months vs. 51.19 months, log-rank P = 0.003). The AA genotype of ERCC1 rs3212986 polymorphism in gastric cancer patients was correlated with a higher risk of death from varying causes by the Cox proportional hazards model, compared to the CC genotype (HR = 6.19, 95% CI = 1.42-30.60). In conclusion, the ERCC1 rs3212986 polymorphism was found to influence the response to chemotherapy and overall survival of gastric cancer patients.

We performed a comprehensive meta-analysis to determine the association between XPD/ERCC2 Lys751Gln polymorphism and melanoma susceptibility. Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between XPD/ERCC2 Lys751Gln polymorphism and melanoma risk. A total of 5,961 cases and 8,669 controls in studies were included in this meta-analysis. All studies were conducted in Caucasian populations. Allele model (Lys vs. Gln: P = 0.53; OR = 0.98, 95% CI = 0.91-1.05), and homozygous model (Lys/ Lys vs. Gln/Gln: P = 0.32; OR = 0.93, 95% CI = 0.81 to 1.07) did not show increased risk of developing melanoma. Similarly, dominant model (Lys/ Lys+Lys/Gln vs. Gln/Gln: P = 0.18; OR = 0.93, 95% CI = 0.83 to 1.03) and recessive model (Lys/ Lys vs. Lys/Gln+Gln/Gln: P = 0.73; OR = 0.98, 95% CI = 0.88 to 1.09) failed to show increased risk of developing melanoma. Our pooled data suggest that there was no evidence for a major role of XPD/ERCC2 Lys751Gln polymorphism in the pathogenesis of melanoma among Caucasian populations.

Genetic variability of DNA repair mechanisms influences chemotherapy treatment outcome of gastric cancer. We conducted a cohort study to investigate the role of ERCC1-ERCC2 gene polymorphisms in the chemotherapy response and clinic outcome of gastric cancer. Between March 2011 and March 2013, 228 gastric patients who were newly diagnosed with histopathology were enrolled in our study. Genotypes of ERCC1 rs11615, rs3212986, rs2298881 and ERCC2 rs3212986 were conducted by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. We found that individuals carrying TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 were associated with better response to chemotherapy and longer survival time of gastric cancer. Moreover, individuals with AA genotype of ERCC2 rs1799793 were correlated with shorter survival of gastric cancer. In conclusion, ERCC1 rs11615, rs2298881 and ERCC2 rs1799793 polymorphism play an important role in the treatment outcome of gastric cancer.

The Asn118Asn (rs11615) variant in the ERCC1 gene, and the Lys751Gln (rs13181) and Asp312Asn (rs1799793) variants in the ERCC2 gene have been associated with the development of varied types of cancer. The aim of the present study was to test for any association between the ERCC1 and ERCC2 gene variants and three different types of cancer in Mexican-mestizo patients. Patients and their respective controls were formed into three groups: The osteosarcoma group, with 28 patients and 97 controls; the colorectal group, with 108 patients and 119 controls; and the breast cancer group, with 71 patients and 74 controls. Genotyping was performed using TaqMan probes and quantitative polymerase chain reaction. Allele and genotype frequencies were compared using a χ 2 test. Only one SNP (rs1799793) was found to be associated with breast cancer. This is the first study analyzing the SNPs in ERCC1 and ERCC2 genes and the susceptibility to cancer in Mexican-mestizo patients with osteosarcoma, and colorectal and breast cancer.

Aim of this study was to analyze the correlation between polymorphisms of ERCC2 and ERCC5 genes and efficiency of repair of oxidative DNA damage with the risk of colorectal cancer (CRC). Experimental material was peripheral blood and tumor slices from CRC collected from 235 patients, 240 people without any cancer were control group. Distribution of polymorphisms of ERCC2 and ERCC5 genes in patients with CRC and healthy subjects, as well as level of oxidative DNA damage in patients and in healthy controls was performed. It has been found that the genotype 751Gln/Gln and allele Gln of ERCC2 gene and allele Asp of 312Asn/Asp polymorphism of ERCC2 gene may be associated with an increased risk of colorectal cancer. Reduced DNA repair efficiency was also demonstrated, which can confirm the important role of oxidative damage and polymorphisms of ERCC2 and ERCC5 genes in the pathogenesis of CRC. In summary, it is critical to establish a link between gene polymorphisms in repair of oxidative DNA damage with the risk of cancer. This in future will allow for diagnostic tests which will let to identify persons with high risk of developing cancer and thus effectively implement prophylactic treatment.

Objective: : Several previous studies have reported the role variant of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms in the risk of glioma, but the results of these studies are inconsistent. Therefore, we aimed to conduct a meta-analysis to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 on the risk of glioma., Methods: A comprehensive research was conducted through the databases of Pubmed, EMBASE and the China National Knowledge Infrastructure (CNKI) platforms until June 1, 2014, including 14 eligible case-control studies., Results: Our meta-analysis found that ERCC1 rs3212986 AA genotype was significantly associated with increased risk of glioma compared with CC genotype, and the pooled OR (95%CI) was 1.29(1.07-1.55). By subgroup analysis, ERCC1 rs3212986 AA genotype was found to be significantly correlated with increased glioma risk in Chinese population (OR=1.37, 95%CI=1.07, 1.55), Similarly, we found that ERCC2 rs13181 GT and TT genotypes were significantly associated with increased risk of glioma in Chinese population, with ORs(95%CI) of 1.47(1.17-1.85) and 1.50(1.02-2.22). But ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms had no significant association with glioma risk in Caucasian populations. By begg's funnel plot, we found that no publication bias was existed in this meta-analysis., Conclusion: Our meta-analysis suggested that ERCC1 rs3212986 and ERCC2 rs13181 polymorphism play an important risk factor for brain tumor development in Chinese population, but no association in Caucasian populations.

Background: A genetic predisposition to acute lymphoblastic leukemia (ALL) in childhood is well established. Currently known risk loci, however, explain only one third of the estimated total risk related to common genetic variations., Procedure: We genotyped 1,421 polymorphisms in 407 candidate genes from the SNP500Cancer database (National Cancer Institute) using the Illumina Cancer SNP Panel. We investigated 78 cases (aged 0-19 years at diagnosis, and mixed ethnic background) of childhood B-precursor ALL and compared genotype data with those of 1,417 HapMap controls. To account for the ethnic diversity of the study population, structured association by genetically matching cases and controls using identity-by-state similarity was used. Case-control association analyses were performed using Cochran-Mantel-Haenszel tests, adjusted for the population substructure., Results: Common variations rs6966 (3' UTR of PPP1R13L, chr 19q13.32, P = 4.55 × 10(-9)) and rs414580 (intron 2 of MSR1, chr 8p22, P = 6.09 × 10(-8)) were significantly associated with ALL. These SNPs remained significant after adjustment for multiple testing. The SNP rs6966 tags a haplotype block which includes SNPs in PPP1R13L and ERCC2 genes, which are related to DNA repair and cell survival. rs6966 and rs414580 conferred allelic odds ratios of 3.74 (95% confidence interval [CI] 2.31-6.04) and 3.93 (95% CI 2.31-6.69), respectively., Conclusions: These findings reveal two independent novel susceptibility loci for childhood ALL., (© 2014 Wiley Periodicals, Inc.)

Background: Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite several factors such as ionizing radiation exposure or rare genetic syndromes have been associated with the development of glioblastoma, no underlying cause has been identified for the majority of cases. We thus aimed to investigate the role of DNA repair polymorphisms in modulating glioblastoma risk., Methods: Genotypic and allelic frequencies of seven common polymorphisms in DNA repair genes involved in nucleotide excision repair (ERCC1 rs11615, ERCC2 rs13181, ERCC6 rs4253079), base excision repair (APEX1 rs1130409, XRCC1 rs25487), double-strand break repair (XRCC3 rs861539) and mismatch repair (MLH1 rs1800734) pathways were analyzed in 115 glioblastoma patients and 200 healthy controls. Haplotype analysis was also performed for ERCC1 rs11615 and ERCC2 rs13181 polymorphisms, located on the same chromosomal region (19q13.32)., Results: Our results indicated that carriers of the ERCC2 Gln/Gln genotype were associated with a lower glioblastoma risk (OR=0.32, 95% CI 0.12-0.89; P=0.028), whereas carriers of the MLH1 AA genotype were associated with an increased risk of glioblastoma (OR=3.14, 95% CI 1.09-9.06; P=0.034). Furthermore, the haplotype containing the C allele of ERCC2 rs13181 polymorphism and the T allele of ERCC1 rs11615 polymorphism was significantly associated with a protective effect of developing glioblastoma (OR=0.34, 95% CI 0.16-0.71; P=0.004)., Conclusions: These results pointed out that MLH1 rs1800734 and ERCC2 rs13181 polymorphisms might constitute glioblastoma susceptibility factors, and also suggested that the chromosomal region 19q could be important in glioblastoma pathogenesis., (Copyright © 2013. Published by Elsevier B.V.)

Many studies have reported the role of xeroderma pigmentosum group D (XPD) with prostate cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk. A total of 8 studies including 2620 cases and 3225 controls described Asp312Asn genotypes, among which 10 articles involving 3230 cases and 3582 controls described Lys751Gln genotypes and were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, a significant association between prostate cancer risk and XPD Asp312Asn polymorphism was found. For Asp312Asn polymorphism, in the stratified analysis by ethnicity and source of controls, prostate cancer risk was observed in co-dominant, dominant and recessive models, while no evidence of any associations of XPD Lys751Gln polymorphism with prostate cancer was found in the overall or subgroup analyses. Our meta-analysis supports that the XPD Asp312Asn polymorphism contributed to the risk of prostate cancer from currently available evidence. However, a study with a larger sample size is needed to further evaluate gene-environment interaction on XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk., (© 2013.)