Excision Repair Cross-complementing Gene Research Articles

Mechanistic study of lncRNA UCA1 promoting growth and cisplatin resistance in lung adenocarcinoma

AimThis study aimed to explore the mechanism of LncRNA urothelial carcinoma-associated 1 (UCA1) promoting cisplatin resistance in lung adenocarcinoma (LUAD).MethodThe UCA1 expression level in LUAD cell lines was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). We overexpressed UCA1 in A549 cells and downregulated UCA1 in A549/DDP cells by the lentivirus‑mediated technique. Subsequently, in vitro, and in vivo functional experiments were performed to investigate the functional roles of UCA1 in the growth and metastasis of LUAD cell lines. Furthermore, RNA pulldown, mass spectrometry, and RNA immunoprecipitation technique were performed to analyze various downstream target factors regulated by UCA1.ResultsThe results revealed a higher UCA1 expression level in A549/DDP cells and LUAD tissues than in A549 cells and adjacent cancer tissues. UCA1 expression was significantly associated with distant metastasis, clinical stage, and survival time of patients with LUAD. UCA1 overexpression significantly increased the proliferation, invasion, clone formation, and cisplatin resistance ability and enhanced the expression levels of proliferating cell nuclear antigen and excision repair cross-complementing gene 1 in A549 cells. However, these trends were mostly reversed after the knockdown of UCA1 in A549/DDP cells. Tumorigenic assays in nude mice showed that UCA1 knockdown significantly inhibited tumor growth and reduced cisplatin resistance. Enolase 1 was the RNA-binding protein (RBP) of UCA1.ConclusionBased on the results, we concluded that UCA1 promoted LUAD progression and cisplatin resistance and hence could be a potential diagnostic marker and therapeutic target in patients with LUAD.

Expression patterns and prognostic significances of RRM1 and ERCC1 in pancreatic carcinoma and cholangiocarcinoma.

Aggressive pancreatobiliary tumors often require oxaliplatin-based therapies, instead of standard gemcitabine-based therapy and biomarker studies at diagnosis to decide the appropriate therapeutic regimen. The ribonucleotide Reductase catalytic subunit M1 (RRM1) and excision repair cross-complementing gene-1 (ERCC1) are related to DNA synthesis and repair and essential in this regard. However, apart from the therapeutic benefit, their prognostic implication is controversial. In this retrospective study, paraffin-embedded tissue from 51 cases of pancreatic cancer and 29 cases of cholangiocarcinoma were evaluated for RRM1 and ERCC1 expression by immunohistochemical technique along with 18 control pancreatic and biliary tissues. The semiquantitatively H score was calculated based on stain distribution and stain intensities. Both RRM1 and ERCC1 expression were high in tumor epithelium than in controls (RRM1: the difference was statistically significant in cholangiocarcinoma (P = 0.008); ERCC1: the difference was statistically significant both in pancreatic and cholangiocarcinoma (P < 0.05)]. However, no correlation was noted between RRM1 and ERCC1-low and high tumors with histological markers of prognosis and overall survival in these patients. The present study adds further evidence against the controversy that if RRM1 and ERCC1 expression in pancreatic and biliary carcinomas have any prognostic significance apart from their proven therapeutic benefits in these tumors.

Correlation between gene polymorphisms of excision repair cross-complementing gene 1 and excision repair cross-complementing gene 2 and susceptibility to bladder cancer in Chinese population

Objective To investigate the relationship between single nucleotide polymorphisms of excision repair cross-complementing gene (ERCC) 1 (rs3212986) and ERCC2 (rs13181) gene and bladder cancer susceptibility in Chinese population. Methods A total of 194 patients with bladder cancer (case group) and 240 healthy subjects (control group) were enrolled. In the case group, there were 143 males and 51 females, 85 cases under 50 years old and 109 cases over 50 years old, body mass index (BMI) <25 154 cases and BMI ≥25 40 cases, 119 cases without smoking history and 75 cases with smoking history, 122 cases without drinking history and 72 cases with drinking history, 179 cases without family tumor history and 15 cases with family tumor history. In the control group, there were 145 males and 95 females; 121 cases under 50 years old and 119 cases over 50 years old, BMI <25 201 cases and BMI ≥25 39 cases, 176 cases without smoking history and 64 cases with smoking history, 169 cases without drinking history and 71 cases with drinking history, 224 cases without family tumor history and 16 cases with family tumor history. The genotypes of ERCC1 rs3212986 and ERCC2 rs13181 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between each genotype and the risk of bladder cancer was explored. Results There was a statistically significant difference in the distribution of ERCC1 rs3212986 genotype between the two groups (χ2=6.010, P 0.05). Conclusion The ERCC1 rs3212986 gene polymorphism affects the occurrence of bladder cancer in the codominant and recessive models. The ERCC2 rs13181 gene polymorphism is not associated with the risk of bladder cancer. Key words: Bladder cancer; Gene polymorphism; Excision repair cross-complementing gene

Clinical Role of Excision Repair Cross-Complementing 1 Gene Expression in Resected Esophageal Squamous Cell Carcinoma: A Meta-Analysis.

To explore the relationship between excision repair cross-complementing 1 (ERCC1) gene expression and clinical pathological parameters and prognosis of esophageal squamous cell carcinoma (ESCC) patients who received the surgical therapy. To identify relevant articles, a systematic literature retrieval was conducted in several databases, including the Embase, Web of Science, Cochrane Library, PubMed, VIP, Wanfang, and CNKI. The association of ERCC1 gene expression with clinicopathological characteristics and survival was assessed by the pooled relative risk (RR) and hazard ratio (HR) with the corresponding 95% confidence interval (CI), respectively. Sensitivity analysis was conducted to assess the stability of pooled results. Begg's funnel plot and Egger's test were applied to detect potential publication bias. A total of nine studies involving 746 patients were included in our meta-analysis, and all patients were from Asian countries, including China, Korea, and Japan. The results indicated that ERCC1 gene expression was significantly associated with lymph node metastasis (RR = 1.30, 95% CI 1.11-1.53; P = 0.002), higher TNM stage (RR = 1.23, 95% CI 1.06-1.43; P = 0.006), worse overall survival (HR = 2.40, 95% CI 1.32-4.37; P < 0.001), and disease-free survival (HR = 1.67, 95% CI 1.15-2.41; P = 0.007). Sensitivity analysis manifested that the pooled results were stable and no significant publication bias was observed. ERCC1 gene expression is significantly related to tumor stage and prognosis in resected ESCC patients from Asian countries. More prospective studies with larger samples are needed to testify our findings.

Expression of ERCC1 and TYMS in colorectal cancer patients and the predictive value of chemotherapy efficacy.

The present study investigated the expression of excision repair cross-complementing gene 1 (ERCC1) and thymidylate synthase (TYMS) in patients with colorectal cancer and the predictive value of chemotherapy. Eighty patients with colorectal cancer chemotherapy admitted to Binzhou Medical University Hospital from June 2013 to June 2015 were randomly selected, and 80 cancer tissues and 68 adjacent tissues were taken for analysis. RT-qPCR was used to detect ERCC1 as well as the expression level of TYMS. The relationship of the expression level with the chemotherapy efficacy, clinical pathology and survival time in colorectal cancer patients receiving standard chemotherapy, was compared. The expression of ERCC1 and TYMS mRNA in cancer tissues was significantly higher than that in the adjacent tissues (P<0.05). There was no correlation between ERCC1 mRNA expression, TYMS mRNA and clinicopathological features of colorectal cancer (P>0.05). The predictive effect of ERCC1 on colorectal cancer chemotherapy was 0.919 (95% CI, 0.862–0.976), P<0.001. The AUC of TYMS for predicting the efficacy of chemotherapy on colon cancer was 0.831 (95% CI, 0.735–0.926), and both had higher predictive values. The expression levels of ERCC1 and TYMS mRNA in 80 patients with colorectal cancer were divided into the low and high expression groups. The 3-year survival rate of patients in the low expression group was significantly higher than that in the high expression group, and the difference between the two groups was statistically significant (P<0.05). ERCC1 and TYMS had a high predictive value for the efficacy of chemotherapy in patients with colorectal cancer, and patients with lower expression of ERCC1 and TYMS had improved 3-year survival rates than patients with higher expression. Therefore, for patients with colorectal cancer, ERCC1 and TYMS can be used as predictors of the efficacy of chemotherapy.

Relationship between Expression of ERCC1 and Effect of Cisplatin Concurrent Chemoradiation in Stage II-IIIA Nasopharyngeal Carcinoma

To investigate the relationship between the expression of excision repair cross-complementing gene 1 (ERCC1) mRNA and protein and the effect of cisplatin concurrent chemoradiation (CCRT) in patients with stage II-IIIA nasopharyngeal carcinoma (NPC). From June 2012 to June 2015, 78 patients with histologically diagnosed stage II-IIIA NPC (7th AJCC stage) were recruited. Immunohistoehemistry and RT-PCR methods were used to detect the expression of ERCC1 protein and mRNA in tumor tissues of these patients before CCRT and correlate with treatment outcomes. The primary endpoints included tumor response by RECIST 1.1 criteria and overall survival (OS). Survivals were calculated with Kaplan-Meier method. The differences between survivals were calculated by Log-rank test. The differences between groups were analyzed using the χ2 test. All statistical tests were two-side. Of 78 patients, 36 patients were positive in expression of ERCC1 protein (46.15%). The expression of ERCC1 protein was not associated with gender, age, T stage and N stage (p>0.05). There were 63 patients with complete response (CR), 7 with partial response (PR), 4 with stable disease (SD), and 4 with disease progression (PD). In 42 patients with negative ERCC1 expression, 41 had CR and PR (97.62%). In comparison, only 29/36 (80.56%) patients with positive ERCC1 protein achieved CR and PR (p=0.036). The expression of ERCC1 mRNA ranged from 0.456 to 1.412 (median 1.119), which was not associated with gender, age, T stage, and N stage (p>0.05). Patients with low ERCC1 mRNA expression (< median) had higher CR and PR (40/41 versus 30/37 for high expression, p=0.043). The 5-year OS for all patients was 91.03%. The 5-year OS for those with negative ERCC1 protein expression was 92.86% versus 88.98% for those with positive ERCC1 protein (p=0.831). The 5-year OS for those with low ERCC1 mRNA expression was 92.68% versus 89.19% for those with high ERCC1 mRNA expression (p=0.887). The expression of ERCC1 protein and mRNA correlated with poorer response to concurrent cisplatin chemoradiation in stage II-IIIA NPC. They were not correlated with 5-year OS possible due to small patient sample size and excellent treatment outcomes of these patients.

Clinical research of individualized therapy in advanced esophageal cancer based on the ERCC1 C8092A genotype.

The present study aimed to explore the role and clinical value of the detection of Excision repair cross-complementing 1(ERCC1) C8092A polymorphisms in individualized therapy of patients with advanced esophageal cancer. A total of 127 patients with advanced esophageal cancer were enrolled between January 2010 and January 2014 in Anhui Provincial Hospital. Patients were randomly assigned in a 1:2 ratio to a standard treatment group or an individualized treatment group, respectively, prior to ERCC1 C8092A assessment. Patients in the standard treatment group were treated with paclitaxel and cisplatin. The DNA was obtained from the peripheral blood of individualized treatment patients, amplified by PCR and sequenced to determine the ERCC1 C8092A polymorphism prior to the administration of chemotherapies. Patients with the ERCC1 C8092A genotype of A/A or A/C received paclitaxel and cisplatin, and those with the genotype of C/C received paclitaxel and fluorouracil. The primary endpoint was response rate (RR). The secondary endpoints included toxicity of chemotherapy, progression-free survival (PFS) and overall survival (OS) times. Differences between the groups were evaluated by χ2 test. Differences in survival were analyzed by Kaplan-Meier survival curves. The survival rate was analyzed by log-rank test. Follow-up data was obtained until December 2015. The RR was obtained for 15 patients (34.8%) in the standard treatment group and 45 patients (53.6%) in the individualized treatment group (χ2=3.095; P=0.046). For adverse events, nausea and vomiting and anemia were significantly decreased in the individualized treatment group compared with the standard treatment group (P=0.001 and P=0.004, respectively). The median progression free survival time was 4.4 months [95% confidence interval (CI)3.8-5.0 months] in the standard treatment group and 6.6 months (95% CI, 5.8-7.4 months) in the individualized treatment group (P=0.018). The median overall survival time was 11.4 months (95% CI, 10.1-12.7 months) in the standard treatment group and 14.2 months (95% CI, 13.2-15.2 months) in the individualized treatment group (P=0.008). The RR, toxicity of chemotherapy, PFS and OS were significantly improved in the individualized treatment group compared with the standard treatment group. Detection of ERCC1 gene polymorphisms maybe performed for patients with advanced esophageal cancer to improve individualized therapy, which requires additional study.

Prognostic values of excision repair cross-complementing genes mRNA expression in ovarian cancer patients

Excision repair cross-complementing (ERCC) genes, key components of the nucleotide excision repair pathway, are regarded as crucial factors for DNA repair capacity. Previous studies have investigated prognostic values of ERCC genes in a number of malignancies. However, the relationship between ERCC genes and prognosis of ovarian cancer patients remains controversial. Therefore, in the current study, we systematically analyze the prognostic values of ERCC genes in ovarian cancer by the Kaplan-Meier plotter, which includes updated gene expression data and survival information of 1656 ovarian cancer patients. Our results showed that high expression of ERCC1 and ERCC8 mRNA was related to a worse overall survival among ovarian cancer patients, especially in late stage and poor differentiation serous ovarian patients. Increased ERCC4 mRNA expression indicated a better overall survival among serous ovarian cancer patients. The other ERCC genes were uncorrelated with prognosis in ovarian cancer. These results indicate that some ERCC genes have critical prognostic values in ovarian cancer.

Polymorphism in ERCC1 confers susceptibility of coronary artery disease and severity of coronary artery atherosclerosis in a Chinese Han population

Excision repair cross-complementing 1 (ERCC1) gene encodes ERCC1 protein, which is mainly responsible for the repair of DNA damage in different diseases including coronary artery atherosclerosis by acting as a rate-limiting element in nucleotide excision repair (NER). Using a three-stage case-control study with 3037 coronary artery disease (CAD) patients and 3002 controls, we investigated associations of three single nucleotide polymorphisms (SNPs) with CAD risk and severity of coronary artery atherosclerosis in Chinese Han population. In the discovery set, the variant allele T of rs11615 was significantly associated with higher CAD risk (adjusted OR = 1.27, P = 0.006) and severity of coronary artery atherosclerosis (adjusted OR = 1.54, P = 0.003). These associations were more remarkable in the merged set (adjusted OR = 1.23, P = 8 × 10−6 for CAD risk; adjusted OR = 1.36, P = 4.3 × 10−5 for severity of coronary artery atherosclerosis). And the expression level of ERCC1 was significantly higher in CAD cases than controls. Multiplicative interactions among SNP rs11615, alcohol drinking, history of T2DM, and history of hyperlipidemia could increase 5.06-fold risk of CAD (P = 1.59 × 10−9). No significant association of rs2298881 and rs3212986 with CAD risk was identified. Taken together, SNP rs11615 in ERCC1 gene might confer susceptibility to CAD and severity of coronary atherosclerosis in a Chinese Han population.

Prognostic and Predictive Value of p21-activated Kinase 6 Associated Support Vector Machine Classifier in Gastric Cancer Treated by 5-fluorouracil/Oxaliplatin Chemotherapy

To determine whether p21-activated Kinase (PAK) 6 is a prognostic and predictive marker in gastric cancer (GC) and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM)–based methods to develop a predictive classifier for chemotherapy (chemotherapy score – CS-SVM classifier). Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS) and overall survival (OS) in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.

Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.

Chemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22-9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21-16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15-41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06-8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002)

AimsGastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. Materials and methodsParaffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. ResultsThere was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). ConclusionLow thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer

The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

A molecular biomarker targeted approach to adjuvant therapy for resected pancreatic adenocarcinoma: Results of a phase II prospective trial.

230 Background: Standard adjuvant treatment for resected pancreatic adenocarcinoma is gemcitabine (Gem) (CONKO-001 trial: Gem vs placebo DFS 13.4 vs 6.7 mo; p&lt;0.001; OS 22.8 vs 20.2 mo; p=0.01). Adding cisplatin (Cis) to Gem has shown increased response rates in the metastatic setting. This benefit may be inhibited by high expression of excision repair cross-complementing gene–1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis chemotherapy, stratifying results by tumor ERCC1 expression. Methods: Patients with resected pancreatic adenocarcinoma at a single institution were enrolled from 2010-2013. Initially, patients received Gem (1000 mg/m2) / Cis (50 mg/m2) Day 1/8/15, Q28d for 6 cycles. After enrolling 5 pts, this was modified to Day 1/15 due to toxicity. Two dose reductions were permitted. Intent to treat analyses were conducted. Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low and high expression groups. Primary outcomes were RFS and OS stratified by ERCC1 expression. Results: Of 22 pts, 16 (73%) had Stage IIB disease, 5 (23%) Stage IIA, and 1 (4%) Stage IA. Thirteen (59%) completed all 6 cycles of therapy, of whom 9 required dose reduction. Of the remaining 9 pts, 4 completed &gt;68% of intended therapy. Grade 3 and 4 toxicity occurred in 13 pts (59%); neutropenia was most common (n=9;41%). Median follow-up was 37.5 mo. Median RFS was 16.7 mo, and OS was 35.5 mo. ERCC1 tumor expression data were available for 20 pts: 15 low (75%) and 5 high (25%). Low compared to high ERCC1 was not associated with improved RFS (12.4 vs 16.7 mo; p=0.68) or OS (Median not reached vs 21.6 mo; p=0.22). Conclusions: Adjuvant gemcitabine/cisplatin is tolerated by patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in the majority of patients. Further prospective trials evaluating Gem/Cis as an adjuvant regimen and ERCC-1 as a biomarker in resected pancreatic adenocarcinoma are warranted. Clinical trial information: NCT01188109.

Overexpression of Excision Repair Cross Complementing-1 Gene May Predict Local Recurrence After Definitive Chemoradiation for Unresectable Non-Small Cell Lung Cancer

Overexpression of Excision Repair Cross Complementing-1 Gene May Predict Local Recurrence After Definitive Chemoradiation for Unresectable Non-Small Cell Lung Cancer

Prognostic Value of Excision Repair Cross-Complementing Gene 1, Dihydropyrimidine Dehydrogenase, and Human Equilibrative Nucleotide Transporter 1 Expression and Their Implications for Adjuvant Treatment in Patients With Ampullary Carcinoma.

The purpose of this study was to characterize the intratumoral expression profiles of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and human equilibrative nucleotide transporter 1 (hENT1) in ampullary carcinomas (ACs) to evaluate their prognostic values and better tailor adjuvant chemotherapy for individual patients with AC after surgery. This study included 49 patients with AC who underwent a curative pancreaticoduodenectomy. Various clinicopathological factors, including ERCC1, DPD, and hENT1, were analyzed in relation to postoperative disease recurrence and the patients' survival. The median recurrence-free survival and overall survival were 24.5 months and 32.4 months, respectively. Multivariate Cox regression analysis of recurrence-free survival identified a DPD expression (hazard ratio [HR], 8.18; 95% confidence interval [CI], 2.00-34.8; P = 0.003) and combined ERCC1/DPD expression (HR, 134.8; 95% CI, 11.8-1920; P < 0.001) as independent predictors of disease recurrence. Multivariate Cox regression analysis of overall survival also identified a DPD expression (HR, 8.48; 95% CI, 1.71-46.3; P = 0.008) and combined ERCC1/ DPD expression (HR, 135.6; 95% CI, 11.8-1940; P < 0.001) as independent predictors of survival. The DPD and ERCC1 expression profile could potentially serve as a useful prognostic biomarker and therapeutic target for surgically resected patients with AC.

Lentivirus-Mediated RNAi silencing targeting ERCC1 reverses cisplatin resistance in cisplatin-resistant ovarian carcinoma cell line.

The aim of the study was to investigate the potential mechanisms that interferencing of excision repair cross-complementing gene 1 (ERCC1) mediated by lentiviral vector in cisplatin-resistant ovarian cancer SKOV3/DDP cells. The human platinum-resistant ovarian carcinoma cell line SKOV3/DDP was transfected by pLVX-shRNA lentivirus. Interference efficiency for ERCC1 by lentiviruses transfection was detected by real-time polymerase chain reaction and western blot assay. CCK-8 assay was used for cell proliferation on cell resistance after transfection with ERCC1. Effects of cell apoptosis and cell cycles were detected by flow cytometry. The expression levels of ERCC1 were significantly suppressed in SKOV3/DDP cells after stably transfecting with shERCC1-recombinant plasmid. The results of cell viability assay demonstrated that interference with ERCC1 gene increased the sensitivity of SKOV3/DDP cells to cisplatin (p<0.01). ERCC1 gene-specific silencing promoted cell apoptosis of SKOV3/DDP cells (p<0.01) detected by flow cytometry. Cell cycle analysis results showed that the proportion of cells in G1 and S phase decreased, while the proportion of G2 phase cells increased in ERCC1-silencing cells. The differences were statistically significant (p<0.01), which demonstrated that stable interferencing with ERCC1 induced the cells arrest in G2 phase after being treated by DDP and silencing the expression of ERCC1 inhibited cell proliferation by preventing the progression of cell mitosis. ERCC1 gene silencing effectively reversed SKOV3/DDP cell resistance to cisplatin and increased sensitivity to cisplatin resistance in cisplatin-resistant ovarian cancer cells. Interference of ERCC1 promoted the apoptosis of SKOV3/DDP cells and prevented cell mitosis by inducing G0/G1 phase arrest. Thus, ERCC1 could be a potential therapeutic target for the therapy of cisplatin-resistant ovarian cancer and it would provide new ideas for epigenetic therapy of drug-resistant epithelial ovarian cancer.

Clinical evaluation of postoperative chemotherapy based on genetic testing in patients with stage IIIA non-small cell lung cancer.

We performed a retrospective analysis to evaluate whether a postoperative chemotherapy selection method based on four tumoral gene expression tests would improve prognosis in patients with stage IIIA non-small cell lung cancer (NSCLC) after surgery. Between January 2007 and July 2011, 148 patients with stage IIIA NSCLC underwent radical lobectomy with four cycles of adjuvant postoperative chemotherapy. Forty-five patients had tailored treatment plans based on the results of tumoral gene expression tests. The tests consisted of quantitative real-time polymerase chain reaction analyses to measure the messenger ribonucleic acid levels of the excision repair cross-complementing gene 1, ribonucleotide reductase Ml, type III β-tubulin, and thymidylate synthase genes in tumor tissues. One hundred and three patients received conventional chemotherapy. Disease responses were assessed after two cycles and every three months after the first four cycles of chemotherapy. The one and two-year survival rates and diesease-free survival (DFS) rates were recorded, and the adverse effects documented. The one and two-year DFS rates in the genetically tested group were better than those in the non-tested group, and the differences were statistically significant (P < 0.05). The two-year Kaplan-Meier DFS curve analysis results were significantly better in the genetically tested group (X(2) = 8.228, P = 0.004). The adverse effects during the treatments were not significantly different (P > 0.05) between the two groups. The chemotherapy selection method based on four tumoral gene expression tests demonstrated its feasibility to improve the efficacy of adjuvant postoperative chemotherapy and benefit stage IIIA NSCLC patients by yielding better DFS without increasing the adverse effects of chemotherapy.

Correlation between ERCC1 expression and concurrent chemotherapy and radiotherapy in patients with locally advanced nasopharyngeal cancer.

In this study, the expression of DNA excision repair cross-complementing gene 1 (ERCC1) in local advanced nasopharyngeal carcinoma has been correlated with the efficacy of concurrent chemoradiotherapy. A total of 76 patients diagnosed with undifferentiated nasopharyngeal carcinoma diagnosed by nasopharyngeal biopsy and undergoing single-agent cisplatin chemotherapy (80 mg/m(2)) with concurrent radiotherapy (on the first, twenty-second, and forty-third day, 5 times per week, mean dose 74 Gy, range 70-78 Gy) at the Affiliated Cancer Hospital of Guangxi Medical University between January and December 2010 were included. After chemoradiotherapy, outcomes and long-term survival were evaluated. Immunohistochemistry was used to detect expression of ERCC1 protein in nasopharyngeal carcinoma. The relationship between the expression of ERCC1 and efficacy of concurrent chemoradiotherapy and long-term survival were analyzed. ERCC1 was expressed in 42.1% of cases. The expression of ERCC1 was correlated with T stage and clinical staging (P < 0.05), but not with gender, age, or N stage. The response rate in the ERCC1-positive and ERCC1-negative groups was 75.0% and 97.7%, respectively (P < 0.05). In the 72 cases with follow-up available, 1-, 2-, and 3-year survival rates were 91.0, 83.3, and 79.0%; they were 92.4, 87.8, 80.5%, respectively, in the ERCC1-positive group, and 87.9, 77.4, 77.4%, respectively, in the ERCC1-negative group. The expression of ERCC1 may be a sensitive prognostic indicator of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma.

Correlation of ERCC1 expression in peripheral blood lymphocytes with outcomes of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy.

Excision repair cross-complementing gene-1 (ERCC1) is a key regulatory enzyme whose expression patterns in tumor tissues are associated with survival in gastric cancer. The present study aimed to evaluate the effects of ERCC1 expression in peripheral blood lymphocytes (PBLs) on the outcome of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy. Tumor and PBL samples from 48 patients treated with adjuvant oxaliplatin-based chemotherapy for gastric cancer were analyzed. Immunohistochemistry was used to assess the expression of ERCC1. After a median follow-up of 18.5 months, the median disease-free survival (DFS) and overall survival (OS) were 12 and 20 months, respectively. Expression of ERCC1 was found in 72.9% (35/48), 56.3% (27/48), and 10.0% (2/20) of tumor tissues, PBLs from gastric cancer patients, and PBLs from controls, respectively. A significant positive correlation between ERCC1 expression in PBL and cancer tissue was found (χ(2) = 12.098, P = 0.001, Pearson contingency coefficient = 0.502). Patients with negative expression of ERCC1 in tumor tissues had a significantly longer median DFS and median OS compared to patients with positive expression of ERCC1 (median DFS, 18 vs 10 months, P = 0.006; median OS, 30 vs 17 months, P = 0.012). In PBLs, high expression of ERCC1 was associated with decreased DFS (9 vs 18 months, P = 0.032), but not OS (16 vs 24 months, P = 0.057). Patients with gastric cancer exhibiting negative expression of ERCC1 are more likely to benefit from oxaliplatin-based adjuvant chemotherapy.