Excision Repair Cross-complementation Group 1 Gene Research Articles

ERCC-1 gene expression as a predictor of outcome following platinum-based chemotherapy in epithelial ovarian cancer (EOC)

5564 Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a crucial component of the nucleotide excision repair pathway which removes cisplatin-induced DNA adducts. High ERCC1 mRNA expression has been associated with platinum resistance in several tumor types. We assessed the relationship between ERCC1 expression and survival in EOC treated with platinum-based chemotherapy. Methods: The Edinburgh Ovarian Cancer Database contains prospectively collected clinical data for all EOC patients treated in SE Scotland. This was screened for patients treated with platinum-containing chemotherapy. 145 archival formalin-fixed, paraffin-embedded (FFPE) tumor samples were recovered and microdissected. mRNA was isolated and quantitative Real Time- PCR was performed for ERCC1. The maximal chi-squared method was used to determine optimal ERCC1 cut-points. Differences in survival between patients whose tumors expressed high/low ERCC1 levels were then compared by Kaplan-Meier analysis. Results: First-line chemotherapy consisted of single agent platinum (69%), platinum-taxane combinations (30%) or a platinum-topotecan combination (1%). Using an ERCC1 cut-point at the 80th percentile to define high expression was found to predict a significantly worse progression-free survival (PFS; p=0.005) and overall survival (p=0.040). In addition, for patients treated with carboplatin and paclitaxel, it was shown that high ERCC1 expression was associated with a worse PFS (p=0.018). Conclusions: ERCC1 gene expression predicts the outcome following platinum-based chemotherapy in EOC. Contrary to the findings of the only other study with >100 patients addressing this issue, the relationship holds for carboplatin and paclitaxel as well as for platinum alone. These findings go some way towards identifying a patient group that is less responsive to standard platinum-based chemotherapy. Alternative treatment strategies should be sought in these patients and tested in the setting of a randomised trial of biomarker guided versus standard therapy. The fact that gene expression analysis can be performed on FFPE tissue increases the applicability of this technology. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics Inc, Response Genetics Ltd Response Genetics Inc, Response Genetics Ltd Response Genetics Inc

Characterization of Functional Excision Repair Cross-Complementation Group 1 Variants and Their Association with Lung Cancer Risk and Prognosis

The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC). Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors. We identified two functional variants in the ERCC1 5'-flanking region, -433T>C and 262G>T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the -433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262T allele. These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs.

Relationship between ERCC1 expression and efficacy of neoadjuvant chemotherapy in the patients with non-small-cell lung cancer.

It has been proven that ERCC1(excision repair cross-complementation group 1)plays an important role in tumor sensitivity to platinum-based chemotherapy.This study was to examine the relationship between ERCC1 expression in NSCLCand efficacy of neoadjuvant chemotherapy. Expression levels of ERCC1 in 73 resected patients with NSCLC were detected with the method of immunohistochemistry. Expression differents of ERCC1 and its relationship with neoadjuvant chemotherapy were analysed with chi-square test, Log-rank test and Cox regression model risk. The positive rate of ERCC1 in NSCLC was 34.25%. Expression rate for ERCC1 in NSCLC treated with neoadjuvant chemotherapy was significantly higher than in those without neoadjuvant group (48.48% vs 20.45%, P =0.025). Compared with the patients with ERCC1-negative tumors, the response rate in the patients with ERCC1-positive tumors was 31.3% vs 58.8%(Chi-Square=2.528,P =0.112), median survival time was 36 months vs 54 months (P =0.118), The 3-year overall survival rate were 43.8% vs 47.1%(Chi-Square=0.029,P =0.866)and The 5-year overall survival rate were 18.8% vs 23.5%(Chi-Square=0.414,P =0.520). COX multivariate regression analysis showed that disease stages, ERCC1 expression and neoadjuvant chemotherapy were independent prognostic facts in the patients. The expression level of ERCC1 is related to the prognosis in patients with NSCLC with neoadjuvant CT. Neoadjuvant CT can induce ERCC1 gene.

Lack of association between DNA repair gene ERCC1 polymorphism and risk of lung cancer in a Chinese population

The ERCC1 (Excision Repair Cross Complementation Group 1) gene is involved in the nucleotide excision repair pathway. This study was designed to examine whether ERCC1 Asn118Asn (G19007A) polymorphism, which has been associated with risk of some cancers among Caucasians, may be associated with risk of lung cancer in a Chinese population. ERCC1 Asn118Asn (G19007A) genotypes were determined in DNA samples from 151 cases and 143 controls. The distribution of genotypes between cases and controls was not associated with an increased risk of lung cancer (AA versus GG: adjusted OR (odds ratio) = 1.41, 95% CI (confidence interval) = 0.76–2.59; AG versus GG: adjusted OR = 0.78, 95% CI = 0.47–1.29; and AA+AG versus GG: adjusted OR = 0.93, 95% CI = 0.73–1.19). The frequency A (0.20) of the A-allele was significantly lower among these Chinese controls than in the Caucasian control populations ( A = 0.54–0.65) (All P < 0.001). No statistically significant effects of age, histological subtype or smoking were found. These findings suggest that ERCC1 Asn118Asn (G19007A) polymorphism may play a limited role for lung cancer in this Chinese population.

Excision repair cross complementing-group 1: Gene expression and platinum resistance (Review) parameters in human breast cancer

Platinum compounds induce their cytotoxic effect by binding to a DNA molecule in the form of a platinum-DNA-adduct. Many previous studies have shown that the level of platinum-DNA-adduct correlats with response to platinum-based chemotherapy. Although the mechanism of platinum resistance in vivo is not clearly understood, laboratory studies on cancer cell lines suggest that nucleotide excision repair (NER) is the main mechanism responsible for this resistance by increased platinum-DNA-adduct removal. NER pathway is a network of many proteins gathered in a DNA-repair system. The excision repair cross complementing-group 1 (ERCC1) gene has the leading role in NER-pathway because of its damage recognition and excision ability. In this report we reviewed the pathway leading to ERCC1 gene transcription and translation in cancer cells when exposed to cisplatin. We summarized data from different cancer cell lines and human cancers showing that the high level of ERCC1-mRNA and/or ERCC1 protein is associated with resistance to platinum compounds with direct impact on cancer patient survival and finally we analyzed drugs interfering with ERCC1 gene expression and causing the reversal of the platinum resistance when given to cancer cells prior to platinum-based chemotherapy.

Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy

ERCC1 (excision repair cross-complementation group 1) and XPD (ERCC2, excision repair cross-complementation group 2) as genes have been known to be belonged to the nucleotide excision repair pathway and therefore related to DNA repair. Polymorphisms in these genes have been rarely evaluated in terms of predicting cancer patient survival. We investigated whether these polymorphisms have an effect on response to chemotherapy and survival in 109 patients with non-small-cell lung cancer treated with cisplatin combination chemotherapy. Polymorphisms of ERCC1 Asn118Asn (C→T), XPD Lys751Gln (A→C) and Asp312Asn (G→A) were evaluated using a SNaPshot kit. As for chemotherapy response, treatment response did not show statistically significant differences between the wild genotypes and the variant genotypes for the ERCC1 and XPD gene. The median survival time of all patients was 376 days (95% CI, 291–488). As for survival rate according to the polymorphism of codon 118 in ERCC1, median survival time in patients showing C/C genotype was 486 days (95% CI, 333– x), which was significantly different from the 281 days (95% CI, 214–376) of patients with the variant genotype (T/T or C/T) ( P=0.0058). Using the Cox-proportional hazards model, the polymorphism of codon 118 in ERCC1, response to chemotherapy, weight loss and performance status effected overall survival significantly ( P=0.0001, 0.0001, 0.0028 and 0.0184, respectively). However, polymorphisms of codons 751 and 312 in the XPD gene did not affect patient survival ( P=0.4711and 0.4542, respectively). Therefore, we suggest that the C/C genotype in codon 118 of ERCC1 is a surrogate marker for predicting better survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.

Modulation of excision repair cross complementation group 1 (ercc-1) mrna expression by pharmacological agents in human ovarian carcinoma cells

Excision repair cross complementation group 1 ( ERCC-1) is a DNA repair gene that is essential for life, and it appears to be a marker gene for nucleotide excision repair activity. Overexpression of ERCC-1 during cisplatin-based chemotherapy is associated with clinical and cellular drug resistance. We therefore began to assess the influence of various pharmacological agents on the induction of ERCC-1 mRNA in A2780/CP70 human ovarian carcinoma cells. Cisplatin exposure in culture resulted in a 4- to 6-fold induction for the steady-state level of ERCC-1 mRNA in A2780/CP70 cells. ERCC-1 mRNA induction was concentration and time dependent. Cyclosporin A and herbimycin A, which suppress c- fos and c- jun gene expressions, respectively, blocked the cisplatin-induced increase in ERCC-1 mRNA. This effect of cyclosporin A or herbimycin A on the down-regulation of ERCC-1 correlates with enhanced cytotoxicity of cisplatin in this system. The products of c- fos and c- jun are components of the transcription factor AP-1 (activator protein 1). 12- O-Tetradecanoylphorbol 13-acetate (TPA), a known AP-1 agonist, induced ERCC-1 mRNA to the same extent as cisplatin, but did not synergize with cisplatin in this regard. The TPA effect was biphasic, with an initial increase during the first 1–6 hr, followed by decreasing mRNA levels at 24–72 hr. These data suggest that the effects of these pharmacological agents on ERCC-1 gene expression may be mediated through the modulation of AP-1 activities.