ERCC1 Rs11615 Research Articles

Molecular Markers for the Prediction of Minor Response to Neoadjuvant Chemoradiation in Esophageal Cancer: Results of the Prospective Cologne Esophageal Response Prediction (CERP) Study.

The aim of this study was to evaluate the predictive value of a single or combination of biomarker(s) for histopathologic non-response to neoadjuvant chemoradiation in esophageal cancer. Patients without response to neoadjuvant chemoradiation for esophageal cancer have no prognostic benefits, but experience time delays and risk side effects. Inclusion criteria for this prospective diagnostic study were patients with cT3,Nx,M0, esophageal squamous cell or adenocarcinoma and planned neoadjuvant chemoradiation (5- fluorouracil, cisplatin, 40Gy) followed by 2-field transthoracic esophagectomy. From pretherapeutic endoscopic tumor biopsies, ERCC1 rs11615 single-nucleotide polymorphism (ERCC1-SNP) and a combination of gene expression marker mRNA (ERCC1, DPYD, ERBB2) were analyzed. ERCC1-SNP was subdifferentiated into homozygous C-allele (CC) and T-allele (TT), and heterozygous C/T carriers. The primary endpoint was the prediction of histopathological minor response (≥10% vital tumor cells in the primary tumor) relative to marker levels. From 2009 until 2013, 320 patients were screened, and 85 patients (SCC n = 29, AC n = 56) were included in the study. Forty-one patients (48%) had major response with 3-year survival rate (3-YSR) of 57% compared with 44 patients with minor response and 3-YSR of 25% (P = 0.001). Patients with ERCC1-SNP CC (n = 8) and TT (n = 37) had similar rates of minor response of 70% and 75%, and a positive predictive value (PPV) of 71% [95% confidence interval (CI 56%-84%)]. PPV increased to 89% (95% CI 73%-96%) when ERCC1-SNP was combined with mRNA markers. ERCC1-SNP in combination with mRNA ERCC1, DPYD, and ERBB2 from pretherapeutic endoscopic biopsies can predict minor response to chemoradiation, as a basis for individualized therapy of advanced esophageal cancer.

Nucleotide excision repair pathway gene polymorphisms are linked to breast cancer risk in a Chinese population.

Polymorphisms in nucleotide excision repair (NER) pathway genes are associated with the risk of breast cancer, but the relevance of these associations appeared to vary according to the ethnicity of the subjects. To systemically evaluate the potential associations between NER polymorphisms and breast cancer risk in a Chinese population, we carried out a case-control study on 450 breast cancer patients and 430 healthy controls. Sequenom MassARRAY was used for genotyping, and immunohistochemistry was performed to detect estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression in tumor tissue. Our results showed that ERCC1 rs11615 (additive model: ORadjusted: 1.36, 95% CI: 1.08-1.71, p = 0.009), XPC rs2228000 (additive model: ORadjusted: 1.39, 95% CI: 1.13-1.72, p = 0.002) and ERCC2/XPD rs50872 (additive model: ORadjusted: 1.32, 95% CI: 1.04-1.67, p = 0.021) were associated with an increased risk of breast cancer. Stratified analysis revealed three polymorphisms (rs11615, rs1800975, and rs50872) to be associated with breast cancer in menopausal females. Three polymorphisms were associated with specific breast cancer grades (rs11615 with grade 3, rs2228000 and rs50872 with grade 1-2). Two polymorphisms (rs2228001 and rs50872) were associated with the risk of breast cancer with negative lymph node involvement. rs1800975 and rs50872 were associated with the risk of ER− and PR− breast cancer, whereas rs11615 was associated with the risk of ER+ and PR+ breast cancer. We found that carriers of the T allele of ERCC1 rs11615, XPC rs2228000 and rs50872, particularly in postmenopausal females, have an increased risk of breast cancer.

A meta-analysis identifies ERCC1 gene polymorphism as a predictor of better patient response to treatment with radiochemotherapy.

This meta-analysis aimed to evaluate whether an association exists between the ERCC1 rs11615 (C>T) polymorphism and patient response to platinum-based chemotherapy and radiation-based chemotherapy. Publications were selected from PubMed and MEDLINE. A meta-analysis was conducted to determine the association between genetic polymorphisms and response to platinum-based chemotherapy and radiation-based chemotherapy by checking the odds ratios (ORs) and 95% confidence intervals (CIs). In our overall analysis, the ERCC1 rs11615 (C>T) polymorphism was not associated with response to platinum-based chemotherapy in five comparison models. In the subgroup analyses by ethnicity, the ERCC1 rs11615 (C>T) polymorphism was shown to be significantly associated with objective response in Caucasian patients treated with platinum-based chemotherapy in the recessive model (TT vs. OR 0.696, 95% CI 0.508-0.954, heterogeneity=0.330), but the association was not observed in the Asian population. The C allele was significantly associated with better response to radiochemotherapy in the recessive model comparison (TT vs. OR 0.724, 95% CI 0.585-0.869, heterogeneity=0.008). Subgroup analysis by cancer type revealed that the C allele of ERCC1 rs11615 predicted a better response in esophageal cancers in two comparison models (T vs. C: OR 0.756, 95% CI 0.648-0.880, heterogeneity=0.653; TT vs. OR 0.457, 95% CI 0.306-0.684, heterogeneity=0.723). Stratified analysis by ethnicity showed a better response in Caucasians in allelic comparison model (T vs. C: OR 0.895, 95% CI 0.819-0.977, heterogeneity=0.095). Together, our results suggest that the ERCC1 rs11615 (C>T) polymorphism was associated with therapeutic response in Caucasian patients and C allele of ERCC1 rs11615 could represent a genetic molecular marker to predict better patient response to radiochemotherapy in recessive model. However, larger prospective randomized trials will be required.

The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk

BackgroundHundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition–unwinding–incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk.ResultsIn screening stage, single-locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 × 10−4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene–gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression.MethodsThis study designed as “screening-verification” experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene.ConclusionsXPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk.

Association between ERCC1 and ERCC2 gene polymorphisms and susceptibility to pancreatic cancer.

We conducted a study to investigate the association between ERCC1 (rs3212986) and ERCC2 (rs13181) gene polymorphisms and the risk of pancreatic cancer in a Chinese population. A total of 217 pancreatic cancer patients and 244 control subjects were recruited from the Nuclear Industry 215 Hospital of Shaanxi Province between February 2013 and December 2014. Genomic DNA was extracted from peripheral blood samples using a TIANamp Blood DNA Kit (Tiangen, Beijing, China) according to the manufacturer's instructions. The ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length of polymorphism. Unconditional logistic regression analyses showed that subjects with the CC genotype of ERCC1 rs3212986 were susceptible to the development of pancreatic cancer when compared with subjects with the AA genotype (OR = 2.57, 95%CI = 1.34-5.02). The ERCC1 rs3212986 gene polymorphism was associated with increased risk of pancreatic cancer in the dominant (OR = 1.54, 95%CI = 1.05-2.28) and recessive (OR = 2.22, 95%CI = 1.20-4.19) models. However, no significant difference was found between the ERCC2 rs13181 polymorphism and the risk of pancreatic cancer in the codominant, dominant, and recessive models. We suggest that the ERCC1 rs3212986 polymorphism increases susceptibility to pancreatic cancer in the codominant, dominant, and recessive models, although further studies are needed to confirm our findings.

Genetic variability of ERCC1 and ERCC2 genes involved in the nucleotide excision repair pathway influences the treatment outcome of gastric cancer.

We conducted a prospective study to investigate whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. Between January 2010 and December 2012, 246 patients with pathologically proven gastric cancer who were receiving platinum-based chemotherapy were recruited from the First Affiliated Hospital of Guangxi Medical University. The genotyping of the gene polymorphisms was conducted using the polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that the AA genotype of ERCC1 rs3212986 was associated with lower rates of complete remission and partial remission following chemotherapy in gastric cancer patients, and the OR (95%CI) was 0.19 (0.06-0.60). We found that the AA genotype of rs3212986 was correlated with higher risk of death from gastric cancer according to the Cox proportional hazards model, and the adjusted HR (95%CI) was 1.60 (0.81-3.16). However, we found no association between ERCC1 rs11615, ERCC2 rs13181, and ERCC2 rs1799793 and overall survival of gastric cancer. In conclusion, the results of the present retrospective study indicate that the ERCC1 rs3212986 gene polymorphism has a significant effect on the pharmacokinetics and treatment outcome of gastric cancer.

Role of single nucleotide polymorphisms of DNA repair genes in susceptibility to pancreatic cancer in Chinese population.

We conducted a case-control study to investigate the role of ERCC1-ERCC5 gene polymorphisms in the risk of pancreatic cancer. This study included 195 patients who were newly diagnosed with histopathologically confirmed primary pancreatic cancer, and 254 controls were recruited from Sir Run Run Shaw Hospital, between January 2012 and December 2014. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Unconditional logistic regression analyses showed that the TT genotype of ERCC1 rs3212986 was associated with an increased risk of pancreatic cancer, and the OR (95%CI) was 2.26 (1.21-4.22). However, we did not find a significant association between ERCC1 rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms and risk of pancreatic cancer. In summary, we found that the presence of the ERCC1 rs3212986 polymorphism correlated with an increased risk of pancreatic cancer.

Role of ERCC2 and ERCC3 gene polymorphisms in the development of osteosarcoma.

We conducted a case-control study to investigate the role of common SNPs in ERCC2 (rs13181 and rs1799793) and ERCC3 (rs4150441 and rs4150506) in the development of osteosarcoma. A 1:2 matched case-control study was conducted. Between January 2012 and December 2013, 141 patients with pathologically diagnosed osteosarcoma and 282 controls were recruited in our study. Genotyping of ERCC2 rs13181 and rs1799793 as well as ERCC3 rs4150441 and rs4150506 were performed using polymerase chain reaction coupled with restriction fragment length polymorphism. The genotype distributions of ERCC2 rs13181 and rs1799793 as well as ERCC3 rs4150441 and rs4150506 showed no significant difference between patients with osteosarcoma and controls, as analyzed by c2 tests. Multivariate logistic regression analysis did not reveal significant associations between ERCC2 rs13181/rs1799793 or ERCC3 rs4150441/ rs4150506 gene polymorphisms and the development of osteosarcoma in codominant, dominant, and recessive models. In conclusion, we did not find any association between ERCC2 or ERCC3 gene polymorphisms and the development of osteosarcoma. Future studies with larger sample sizes may contribute in elucidating the impact of ERCC2 and ERCC3 gene polymorphisms on osteosarcoma risks.

Association between ERCC5 gene polymorphisms and gastric cancer risk in a Chinese population.

We conducted a hospital-based case-control study to investigate the association between 3 common SNPs in the ERCC5 gene (rs1047768, rs751402, and rs17655) and the risk of developing gastric cancer. Between January 2013 and December 2014, samples were collected from 216 gastric cancer patients and 216 control subjects. ERCC5 rs1047768, rs751402, and rs17655 polymorphisms were genotyped by polymerase chain reaction combined with restriction fragment length polymorphism analysis. By conditional logistic regression analysis, the GG genotype of rs17655 was found to be associated with an elevated risk of gastric cancer in a codominant model, and the adjusted OR (95%CI) was 1.96 (1.10-3.50). Moreover, in a dominant model, the CG + GG genotype of rs17655 was correlated with an increased risk of gastric cancer compared to the CC genotype (OR = 1.48; 95%CI = 1.00-2.22). rs1047768 and rs751402 were not significantly correlated with an increased or decreased gastric cancer risk.

Association between ERCC1 and ERCC2 polymorphisms and breast cancer risk in a Chinese population.

We conducted a case-control study to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 gene polymorphisms in the development of breast cancer. Between March 2012 and March 2014, a total of 242 newly diagnosed breast cancer patients with histopathologically confirmed primary breast cancer and 242 healthy controls were recruited. Genotyping of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism analysis. Unconditional logistic regression analyses indicated that the TT genotype of rs3212986 was associated with a higher risk of breast cancer compared to that associated with the GG genotype (OR = 2.05, 95%CI = 1.13-3.78). In dominant and recessive models, we found that the rs3212986 polymorphism was associated with increased risk of breast cancer, and the ORs were 1.50 (95%CI = 1.03-2.18) and 1.74 (95%CI = 1.01-3.11), respectively. In summary, we found that the ERCC1 rs3212986 polymorphism was associated with the development of breast cancer.

Association between ERCC5 gene polymorphisms and gastric cancer risk.

We investigate the role of ERCC5 gene polymorphisms (rs17655 and rs751402) in the development of gastric cancer in a Chinese population. A total of 142 gastric cancer patients whose diagnoses were confirmed by pathology, and 274 control subjects were recruited from Tangshan Gongren Hospital between March 2013 and March 2015. Genotyping of ERCC5 rs17655 and rs751402 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism. Compared with the control subjects, we found that gastric cancer patients were more likely to be older, smoke tobacco, drink alcohol, and suffer from Helicobacter pylori infection. Using a chi-square test, a significant difference was observed in the distribution ofERCC5 rs751402 genotypes between patient and control groups (chi-square = 7.79, P = 0.02). In addition, unconditional multiple logistic regression analysis revealed that the AA genotype of rs751402 significantly increased gastric cancer risk compared to the GG genotype [odds ratio (OR) = 2.61, 95%CI = 1.23-5.49; P = 0.005]. Moreover, we found that the AA genotype correlated with elevated risk of gastric cancer when compared to the GG+AG genotype under a recessive model (OR = 2.21, 95%CI = 1.11-4.39; P = 0.01). In conclusion, we suggest that the ERCC5 rs751402 polymorphism is associated with development of gastric cancer.

ERCC2 rs13181 polymorphism association with glioma susceptibility in a Chinese population.

We conducted a case-control study to investigate the role of ERCC2 rs13181 polymorphism in glioma development. A total of 165 patients who were histopathologically diagnosed to have gliomas and 330 controls were collected at Jiujiang First People's Hospital between July 2012 and June 2014. The ERCC2 rs13181 polymorphism was analyzed using a polymerase chain reaction -restriction fragment length polymorphism assay. By conditional regression analysis, we found that the GG genotype of the ERCC2 rs13181 polymorphism is associated with susceptibility to gliomas when compared to the TT genotype (OR = 2.05, 95%CI = 1.11-3.79). In the recessive model, the GG genotype is associated with an increased risk of gliomas when compared with the TT+TG genotype (OR = 1.87, 95%CI = 1.03-3.37). In conclusion, the ERCC2 rs13181 polymorphism is correlated with an increased risk of gliomas in codominant and recessive models, which suggests that this polymorphism could influence the etiology of gliomas.

A germline predictive signature of response to platinum chemotherapy in esophageal cancer

Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.

ERCC2 polymorphisms and radiation-induced adverse effects on normal tissue: systematic review with meta-analysis and trial sequential analysis.

BackgroundThe relationship between ERCC2 polymorphisms and the risk of radiotoxicity remains inconclusive. The aim of our study is to systematically evaluate the association between ERCC2 polymorphisms and the risk of radiotoxicity.MethodsPublications were identified through a search of the PubMed and Web of Science databases up to August 15, 2015. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between ERCC2 polymorphisms and radiotoxicity. Trial sequential analysis (TSA) and power calculation were performed to evaluate the type 1 and type 2 errors.ResultsEleven studies involving 2584 patients were ultimately included in this meta-analysis. Conventional meta-analysis identified a significant association between ERCC2 rs13181 polymorphism and radiotoxicity (OR = 0.71, 95 % CI: 0.55-0.93, P = 0.01), but this association failed to get the confirmation of TSA.ConclusionsThe minor allele of rs13181 polymorphism may confer a protect effect against radiotoxicity. To confirm this correlation at the level of OR = 0.71, an overall information size of approximate 2800 patients were needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0558-6) contains supplementary material, which is available to authorized users.

Influences of ERCC1, ERCC2, XRCC1, GSTP1, GSTT1, and MTHFR polymorphisms on clinical outcomes in gastric cancer patients treated with EOF chemotherapy.

This study investigated the associations between genetic polymorphisms of six genes involved in DNA repair, detoxification pathways, and fluoropyrimidine metabolism and clinical outcomes in MGC patients receiving EOF treatment. This retrospective study included 108 Chinese MGC patients receiving EOF as first-line chemotherapy. Nine single nucleotide polymorphisms (SNPs) of six genes (ERCC1 rs2298881, ERCC2 rs13181 and rs1799793, XRCC1 rs25487 and rs25489, GSTP1 rs1695, GSTT1 rs2266637, and MTHFR rs1801133 and rs1801131) were genotyped, and the associations between each SNP and clinical outcome were analyzed. XRCC1 rs25487 A allele was significantly associated with progression disease (PD) to EOF (p = 0.002), and patients with AA genotype had significantly poorer progression-free survival (PFS) (p = 0.001) and overall survival (OS) (p = 0.041) compared with patients with the G allele (GG + GA). ERCC2 rs13181 G allele was significantly associated with PD (p = 0.026), and G carriers (GG + GT) tended to have poorer PFS (p = 0.092) than TT homozygotes. ERCC2 rs1799793 GA genotype was associated with unfavorable PFS (p = 0.034) and a tendency toward poorer OS (p = 0.090) compared with GG homozygotes. Patients were categorized as either good (0 risk factors) or poor risk (≥1 unfavorable SNPs) using a prognostic index based on XRCC1 rs25487 AA, ERCC2 rs13181 (GG + GT), and ERCC2 rs1799793 GA genotypes, with median OS and PFS of 534days, 281days (p = 0.009) and 206days, and 123days (p < 0.001), respectively. These results suggest that the prognostic index comprising XRCC1 rs25487, ERCC2 rs13181, and rs1799793 polymorphisms may be a useful predictor of clinical outcomes in MGC treated with EOF.

A Comprehensive Analysis of Influence ERCC Polymorphisms Confer on the Development of Brain Tumors.

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.

Genetic variability of DNA repair mechanisms influences treatment outcome of gastric cancer

The aim of the current study was to investigate the role of polymorphisms in DNA repair pathways on the clinical outcome of gastric cancer patients treated with platinum-based chemotherapy. A total of 380 gastric cancer patients treated with platinum-based chemotherapy were included in the present study. The genotypes of ERCC1 rs11615 (Asn118Asn) and rs3212986 (*197G>T), ERCC2 rs1799793 (Asn312Asp) and rs13181 (Lys751Gln), NBN rs1805794 (Gln185Gln) and rs1063054 (*1209A>C), RAD51 rs1801321 (−61G>T) and rs12593359 (*502T>G), and XRCC3 rs861539 (Thr241Met) were determined by polymerase chain reaction-restriction fragment length polymorphism, according to the manufacturer's instructions. The TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 were found to be associated with improved response to chemotherapy, with an adjusted odds ratio of 1.66 (95% CI, 1.07–2.56) and 1.61 (95% CI, 1.05–2.49), respectively. Based on the results of Cox analysis, patients with TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 exhibited a significantly decreased risk of mortality, with hazard ratios of 1.71 (95% CI, 1.06–2.72) and 1.97 (95% CI, 1.28–3.03), respectively. In conclusion, these results suggest that ERCC1 rs11615 and ERCC2 rs1799793 in the DNA repair pathways may be used as predictive factors of the clinical outcome in gastric cancer patients.

Association of ERCC1 polymorphisms (rs3212986 and rs11615) with the risk of head and neck carcinomas based on case-control studies.

Current data regarding association between ERCC1 polymorphisms and the risk of head and neck squamous cell carcinomas (HNSCC) have shown controversial results. The current study aims to achieve a more accurate estimation of the association between two well-characterized ERCC1 polymorphisms (rs3212986 and rs11615) and HNSCC risk by a meta-analysis of all eligible studies. The meta-analysis was performed by reviewing seven studies on the ERCC1 C8092A (rs3212986) polymorphism including 2055 cases and 2635 controls and four studies on the T19007C (rs11615) polymorphism including 910 cases and 1337 controls. For ERCC1 rs3212986 polymorphism, no significant association with HNSCC was found in overall analysis, but subgroup analysis revealed that a significant association of the rs3212986 polymorphism was found among Asians (A vs. C: OR 0.83; 95% CI 0.70-0.99) but not Caucasians. For ERCC1 rs11615 polymorphism, a significant association with HNSCC (TC + CC vs. TT: OR 1.23; 95% CI 1.03-1.47) was found in overall analysis. Consistently, subgroup analysis revealed that significant associations of the rs3212986 polymorphism were found among Asians (C vs. T: OR 1.32; 95% CI 1.04-1.69) and in laryngeal carcinoma (CC vs. TC + TT: OR 1.32; 95% CI 1.02-1.72). The findings of the meta-analysis indicated that a decreased risk for the ERCC1 rs3212986 polymorphism was found among Asians, and an increased risk for the ERCC1 rs11615 polymorphism was found in overall HNSCC, especially in Asian subgroup and laryngeal site, suggesting that ERCC1 rs3212986 polymorphism in Asians may act as a protective factor and rs11615 polymorphism may be a risk factor for HNSCC.

Technical Reproducibility of Single-Nucleotide and Size-Based DNA Biomarker Assessment Using DNA Extracted from Formalin-Fixed, Paraffin-Embedded Tissues

DNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissues has been used in the past to analyze genetic polymorphisms. We evaluated the technical reproducibility of different types of assays for gene polymorphisms using DNA extracted from FFPE material. By using the MassARRAY iPLEX system, we investigated polymorphisms in DPYD (rs1801159 and rs3918290), UMPS (rs1801019), ERCC1 (rs11615), ERCC1 (rs3212986), and ERCC2 (rs13181) in 56 FFPE DNA samples. By using PCR, followed by size-based gel electrophoresis, we also examined TYMS 5' untranslated region 2R/3R repeats and GSTT1 deletions in 50 FFPE DNA samples and 34 DNAs extracted from fresh-frozen tissues and cell lines. Each polymorphism was analyzed by two independent runs. We found that iPLEX biomarker assays measuring single-nucleotide polymorphisms provided consistent concordant results. However, by using FFPE DNA, size-based PCR biomarkers (GSTT1 and TYMS 5' untranslated region) were discrepant in 32.7% (16/49, with exact 95% CI, 19.9%-47.5%; exact binomial confidence limit test) and 4.2% (2/48, with exact 95% CI, 0.5%-14.3%) of cases, respectively, whereas no discrepancies were observed using intact genomic DNA. Our findings suggest that DNA from FFPE material can be used to reliably test single-nucleotide polymorphisms. However, results based on size-based PCR biomarkers, and particularly GSTT1 deletions, using FFPE DNA need to be interpreted with caution. Independent repeated assays should be performed on all cases to assess potential discrepancies.

DNA repair gene polymorphisms do not predict response to radiotherapy-based multimodality treatment of patients with rectal cancer: a meta-analysis.

: A number of association studies have been carried out to investigate the relationship between genetic polymorphisms in DNA repair genes and response to radiotherapy-based multimodality treatment of patients with rectal cancer. However, their conclusions were inconsistent. The objective of the present study was to assess the role of DNA repair gene genetic polymorphisms in predicting genetic biomarkers of the response in rectal cancer patients treated with neoadjuvant chemoradiation. Studies were retrieved by searching the PubMed database, Cochrane Library, Embase, and ISI Web of Knowledge. We conducted a meta-analysis to evaluate the association between genetic polymorphisms and the response in rectal cancer treated with neoadjuvant chemoradiation by checking odds ratios (ORs) and 95% confidence intervals (CIs). Data were extracted from 5 clinical studies for this meta-analysis. The results showed that XRCC1 RS25487, XRCC1 RS179978, XRCC3 RS861539, ERCC1 RS11615 and ERCC2 RS13181 were not associated with the response in the radiotherapy-based multimodality treatment of patients with rectal cancer (p>0.05). This study shows that DNA repair gene common genetic polymorphisms are not significantly correlated with the radiotherapy-based multimodality treatment in rectal cancer patients.