ERCC1 Protein Expression Research Articles

Analysis of Application of Value of ERCC1 Protein Expression in Pathological Diagnosis of Gastric Cancer Patients

Analysis of Application of Value of ERCC1 Protein Expression in Pathological Diagnosis of Gastric Cancer Patients

Predictive Value of ERCC1 mRNA Level from Receiver-Operator Characteristic and Pretreatment EBV-DNA Virus Load in Stage II Nasopharyngeal Carcinoma Patients Receiving Intensity-Modulated Radiotherapy with Concurrent Cisplatin.

Background: The molecular mechanisms underlying chemoresistance are still poorly understood in nasopharyngeal cancer. The protein expression of ERCC1 in DNA repair genes has been reported related to resistance platinum and predicting treatment outcomes in various malignant carcinomas, but the benefit for predicting outcomes with optimal cutoff value of ERCC1mRNA is controversial. The level of plasma Epstein-Barr virus (EBV) DNA is positively correlated with clinical stages of nasopharyngeal carcinoma (NPC). The predictive value of ERCC1mRNA from receiver-operator characteristic (ROC) and EBV-DNA level for stratified treatment with stage II NPC is exactly unclear. This study aims to assess the predictive value of combined EBV-DNA and ERCC1 in stage II nasopharyngeal cancer (NPC) patients treated with intensity-modulated radiotherapy (IMRT) with concurrent cisplatin, and provide guidance for future stratified treatment. Methods: A total of 86 stage II NPC patients who received IMRT and concurrent cisplatin-based chemotherapy with or without cisplatin-based adjuvant chemotherapy had measurements of ERCC1 mRNA, and pretreatment EBV-DNA levels were analyzed by real-time PCR (RT-PCR). Associations of ERCC1 mRNA and pretreatment EBV-DNA levels with clinical characteristics and survivals were evaluated. Results: Cutoff value of ERCC1 mRNA obtained from ROC curve was used, and there were significant differences in progression-free survival (PFS) and overall survival (OS) and overall response rate (ORR) between high expression group and low expression group (p = 0.021 and 0.030 and 0.000, respectively). Patients with pretreatment EBV-DNA <2000 copies/mL had significantly better PFS and ORR (p = 0.024 and 0.043, respectively) and a marginally significant impact on OS (p = 0.062) than those with pretreatment EBV-DNA ≥2000 copies/mL. Patients were divided into three groups by combination of ERCC1 mRNA and EBV-DNA level: ERCC1 mRNA low expression/pre-EBV-DNA <2000 copies/mL, ERCC1 mRNA low expression/pre-EBV-DNA ≥2000 copies/mL, and ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL. There were significant differences in ORR among the three groups (p = 0.005). The median follow-up was 62 months (range 22-84) with a follow-up rate of 90.70%. In these groups by combination of ERCC1 mRNA and EBV-DNA level, 1, 3, 5-year OS were 100%, 100%, 100%; 100%, 94.1%, 90.9%; and 100%, 85%, 72.9%, respectively (p = 0.038); 1, 3, 5-year PFS were 100%, 100%, 100%; 97.1%, 91.2%, 84.8%; and 95%, 85%, 71.4%, respectively (p = 0.028). Multivariate analysis showed that combination of ERCC1 mRNA and EBV-DNA levels remained independent prognostic factor but not ERCC1 mRNA and EBV-DNA alone. Conclusions: Combined ERCC1 mRNA and pre-EBV-DNA is a better prognostic biomarker in stage II NPC patients treated with concurrent chemoradiation. Patients with ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL may benefit from more aggressive treatment.

Clinical Perspectives of ERCC1 in Bladder Cancer.

ERCC1 is a key regulator of nucleotide excision repair (NER) pathway that repairs bulky DNA adducts, including intrastrand DNA adducts and interstrand crosslinks (ICLs). Overexpression of ERCC1 has been linked to increased DNA repair capacity and platinum resistance in solid tumors. Multiple single nucleotide polymorphisms (SNPs) have been detected in ERCC1 gene that may affect ERCC1 protein expression. Platinum-based treatment remains the cornerstone of urothelial cancer treatment. Given the expanding application of neoadjuvant and adjuvant chemotherapy in locally advanced bladder cancer, there is an emerging need for biomarkers that could distinguish potential responders to cisplatin treatment. Extensive research has been done regarding the prognostic and predictive role of ERCC1 gene expression and polymorphisms in bladder cancer. Moreover, novel compounds have been recently developed to target ERCC1 protein function in order to maximize sensitivity to cisplatin. We aim to review all the existing literature regarding the role of the ERCC1 gene in bladder cancer and address future perspectives for its clinical application.

Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer

Gastric cancers are the third leading cause of cancer mortality in the world. Helicobacter pylori causes over 60 % of all stomach cancers. Colonization of the gastric mucosa by H. pylori results in increased DNA damage. Repair of DNA damage may also be reduced by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can cause carcinogenic mutations. During progression to gastric cancer, gastric epithelium goes through stages of increasing pathology. Determining the levels of DNA repair enzymes during progression to gastric cancer could illuminate treatment approaches. Our aim is to determine the level of gastric expression of DNA repair proteins ERCC1 (a nucleotide excision repair enzyme) and PMS2 (a mismatch repair enzyme) in the presence of H. pylori infection at successive stages of gastric pathology and in gastric cancers. We analyzed gastric tissues of 300 individuals, including 30 without dyspepsia, 200 with dyspepsia and 70 with gastric cancers. The presence of H. pylori, gastric pathology and expression of DNA repair proteins ERCC1 and PMS2 were evaluated.Infection by H. pylori carrying the common cagA gene reduced median nuclear expression of ERCC1 and PMS2 to less than 20 % and 15 % of normal, respectively, in all pathologic stages preceding cancer.ERCC1 and PMS2 nuclear expression was 0–5 % of normal in gastric cancers. H. pylori can cause deficiency of ERCC1 and PMS2 protein expression. These deficiencies are associated with gastric pathology and cancer. This reduction in DNA repair likely causes carcinogenic mutations. Substantially reduced ERCC1 and PMS2 expression appears to be an early step in progression to H. pylori-induced gastric cancer.

ERCC1 expression in advanced colorectal cancer and matched liver metastases

BackgroundPlatinum-based chemotherapy is part of the standard treatment for patients with colorectal cancer. ERCC1 is a potential predictive biomarker for platinum-based chemotherapy. The aim of this study was to examine interobserver agreement on ERCC1 protein expression in primary colorectal cancer as well as corresponding liver metastasis. Furthermore, comparison of ERCC1-expression in primary tumor and the corresponding liver metastasis was performed. MethodsForty patients with primary colorectal cancers and corresponding liver metastases were included. One slide was stained with the anti-ERCC1 antibody, 4F9 clone (DAKO) and evaluated by two gastrointestinal pathology consultants and a pathology registrar separately. Interobserver agreement was evaluated for primary tumors and liver metastases using kappa (κ) statistics. Discordant scorings were reviewed, and consensus was obtained. The expression in primary tumor was compared with the corresponding liver metastases. ResultsFor the primary tumors agreement was found in 85% of the tumors corresponding to an unweighted kappa value of 0,79 (95% CI 0,64-0,94). For the liver metastases agreement was found in 76% corresponding to an unweighted kappa value of 0,64 (95% CI 0,49-0,79). When comparing primary tumors to the corresponding metastases, no concordance in ERCC1-expression was observed. ConclusionInterobserver agreement of ERCC1 expression was good for both primary tumors and liver metastases, which is crucial for a potential predictive biomarker. As no concordance between primary tumor and liver metastases was found it seems to be of high importance to use tissue from actual tumor burden for evaluation of ERCC1 expression. Further studies and correlation to clinical outcome are warranted.

Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours

BackgroundGerm cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines.MethodsTwo hundred seven GCT patients’ specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients’ specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines.ResultsGCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12–1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines.ConclusionsXPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

Significance of ERCC1 and Hormonal Receptor Expression in Ovarian Cancer.

Background & Objectives : Ovarian carcinoma usually has a relatively poor prognosis. A rational approach to identify patients, who are likely to benefit from therapy, is urgently needed. Excision repair cross-complementation group 1 enzyme (ERCC1) has been proposed as a molecular predictor of clinical resistance to platinum-based chemotherapy. Steroid hormone receptors are important determinants of prognosis and predictive behavior in tumor tissues of several origins. The present study aimed to investigate the expression profile of ERCC1, ER & AR in patients with Ovarian carcinoma and their association with patient outcome. Methods : This is a prospective study which included 77 patients with ovarian carcinoma who were treated with platinum based chemotherapy at the National Cancer Institute (NCI) in Egypt during the period 7/2016- 7/2018. We evaluated the expression of ER, AR, and Excision repair cross-complementation group 1 enzyme (ERCC1) by immunohistochemistry. Expression profiles were compared to clinical, histologic and prognostic factors, the clinical outcome and survival. All patients received platinum containing chemotherapy regimen. Result : Of the 77 patients with ovarian cancer, 66.2 % (51/77) were ERCC1-positive, 49.4 % (38/77) were AR positive & 75.3 % (58/77) were ER positive. Platinum resistance was found in eight of the tumors with positive ERCC1 protein expression compared with two among the patients with negative tumor staining for ERCC1 (P = 0.643). There was significant association between ER & AR expression and pathological subtypes (p = 0.004, 0.007) respectively. There were no significant association between ER, AR& ERCC1 expression and PFS (P = 0.447,P = 0.162, P = 0.508 respectively) or OS (P = 0.781, P = 0.569, P = 0.381 respectively). Based on Cox proportional hazards regression analysis ERCC1, ER &AR were not independent factors affecting the prognosis of patients with ovarian carcinoma. Conclusion : These results demonstrate that positive ERCC1 expression is not associated with clinical resistance to platinum-based chemotherapy, ERCC1, AR& ER expression are not independent factors affecting the prognosis of patients with epithelial ovarian tumors and not associated with survival benefits. J. Med. Invest. 67 : 391-398, August, 2020.

The Significance of Molecular Biomarkers on Clinical Survival Outcome Differs Depending on Colon Cancer Sidedness.

This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.

Multiplatform profiling of pancreatic neuroendocrine tumors: Correlative analyses of clinicopathologic factors and identification of co-occurring pathogenic alterations.

Multi-omic profiling of pancreatic neuroendocrine tumors (PanNETs) was performed to correlate genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identify novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management. PanNETs referred to Perthera, Inc. having undergone molecular profiling for precision matched therapeutic purposes were screened. Correlative analyses were performed using Fisher's exact test across individual pathogenic alterations or altered molecular pathways and clinicopathologic variables. Associations were visualized by hierarchical clustering. Prognostic associations with overall survival (OS) were identified using Cox regression for pathogenic alterations and pathway-level alterations. Hazard ratios (HR) and odds ratios (OR) were reported with 95% confidence intervals (CI). From 12/2014-1/2019, 46 patients with predominantly locally advanced and metastatic PanNETs were included. MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs and metastatic disease at diagnosis (p ≤ 0.05). Genomic alterations associated with increased replicative stress (primarily driven by RB1 and TP53) correlated with higher grade (OR 6.87 [95% CI: 1.57-35.18], p = 0.0043) and worse OS (HR 13.62 [95% CI: 1.51-122.5], p = 0.0198). Other significant associations included: ERCC1 protein expression with DAXX or MEN1 alterations (NGS), PTEN (NGS) with ARID1A or TP53 alterations (NGS), and history of diabetes coincided with cell cycle pathway alterations but was mutually exclusive with replicative stress pathway alterations. We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.

Abstract 4023: Co-occurring mutations in recurrent/persistent head and neck squamous cell carcinoma (HNSCC) patients

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and lacks effective targeted therapies. HPV(-) patients have a 50-60% recurrence rate and could benefit from adjuvant therapy. Although HPV(+) patients have a significantly better survival, 20% have persistent/recurrent disease. Therefore, biomarkers could potentially help identify patients that would benefit from adjuvant targeted agents. Our objective was to evaluate if the mutational and biomarker analysis of tumor samples from OPSCC patients predict recurrence and/ or persistence in patients undergoing definitive therapy with curative intent. 44 advanced stage OPSCC patients that underwent comprehensive genomic profiling by Caris Life Sciences were included in this retrospective study. Next Generation Sequencing (NGS) on genomic DNA from FFPE tumors was performed using the Illumina Nextseq (592-gene, n=17)/MiSeq (44-gene, n=23) platform. Tumors were analyzed for total mutational load (TML), CNV’s and microsatellite instability status. IHC for tumor protein expression of ERCC1, PD-L1, RRM1, TrkA/B/C, TS and TUBB3 was performed using automated platforms. The ASCO/CAP scoring criteria and the cutoff points from published evidence was used in IHC evaluation. Of the 44 patients, 27 were HPV(+) tumors and 11 had HPV(-) disease. Patients with lack of progression free survival data were excluded. Only 4 patients in the entire cohort harbored a pathogenic PIK3CA mutation. Among HPV(+) patients, 22 patients were TP53 WT and 2 patients were found to be TP53 mutant. Although there was no significant change in the TML in smokers compared to nonsmokers (mean 8.77 vs 6.5, respectively; p=0.253), TML was higher in HPV(-) smokers compared to HPV(+) nonsmokers (mean 10.33 vs 6.5, p=0.0661). Our study presented a higher incidence of recurrent/persistent disease in the Caucasians (60%) in comparison to African-Americans (21%). Considering the sample size in the current study, the racial difference in outcomes appears likely to be present regardless of HPV status or disease state. The co-occurrence of multiple deleterious mutations was observed in 70% of the non-responders. Particularly, mutations in CHEK2, PTCH, MUTYH were noted in 50% of the recurrent/persistent patients. CNV mutations in SMAD2, MALT1, NFKBIA in 50% of the recurrent/persistent patients were found. The co-occurrence of multiple mutations were absent in responders in spite of an appreciable sample size in the responder group (n=12). This study also affirmed an improved prognosis in patients with HPV(+), with higher expression of TUBB3, and with positive expression of PD-1 in the tumors. Co-occurrence of multiple deleterious mutations were associated with patients who did not respond to therapy. Therefore, combination rescue therapies that can target multiple pathways to abrogate the mutational effects can aid/enhance therapeutic benefits in HNSCC patients. Citation Format: Alok R. Khandelwal, Kelsey Poorman, Tara Moore-Medlin, Xiaohui Ma, Abhijit Gundale, Ronald Horswell, San Chu, Michelle Winerip, Cherie-Ann O. Nathan. Co-occurring mutations in recurrent/persistent head and neck squamous cell carcinoma (HNSCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4023.

CORRELATION OF HISTOPATHOLOGIC RESPONSE AND PROGNOSTIC MARKERS WITH THE SURVIVAL IN LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER PATIENTS TREATED WITH NEOADJUVANT CHEMOTHERAPY

Objective: We aimed to determine the response and prognosis to neoadjuvant chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) who had received neoadjuvant therapy and to determine the relationship with prognosis and treatment response of the expression of excision repair cross-complementation group 1 protein (ERCC1) and Ribonucleotide reductase regulatory subunit M1 (RRM1) protein.Material and Methods: Twenty-seven patients with stage III NSCLC who received neoadjuvant chemotherapy and had been operated between 2003 and 2013 were included in this study. Lung tissue biopsies were evaluated by immunohistochemical methods for ERCC1 protein expression in patients who received cisplatin and RRM1 protein expression who received gemcitabine.Results: Median age was 59 (45-75). Nineteen patients (70.4%) were at stage IIIA and eight patients (29.6 %) were at stage IIIB. All patients received neoadjuvant cisplatin-based chemotherapy. Fifteen patients (55.6%) relapsed during follow-up. The median follow-up time was 36 months. The median disease-free survival (DFS) was 26.6 months, overall survival (OS) was 48 months. From the perspective of stage IIIA and IIIB DFS (p=0.379) and OS (p=0.69) did not differ significantly. Sixteen patients’ (59.3%) viable tumor ratio was ≤10%, 11 patients’ (40%) viable tumor ratio was &amp;gt;10%. When considered from this point of view DFS (p=0.16) and OS (p=0.097) showed no difference. More patients survived in the low ERCC1 expression group. Patients with low ERCC1 expression and patients with high ERCC1 expression showed no difference in terms of survival.Conclusion: Patients with high RRM1 expression showing resistance to gemcitabine and with low RRM1 expression had similar survival rates. In patients with stage III NSCLC who received neoadjuvant chemotherapy, OS and DFS durations longer than literature were found.

Systematic immunohistochemical screening for mismatch repair and ERCC1 gene expression from colorectal cancers in China: Clinicopathological characteristics and effects on survival.

BackgroundWe performed a systematic screening of colorectal cancer (CRC) tissues to investigate whether mismatch repair (MMR) status and ERCC1 protein expression could be predictive of clinical outcomes for these patients following the recommendation of The Evaluation of Genomic Applications in Practice of Prevention (EGAPP).MethodsThe expression of four MMR genes and ERCC1 were assessed by immunohistochemistry (IHC) from cancer tissue samples of 2233 consecutive CRC patients.ResultsWe observed that most CRC patients with a proficient MMR (pMMR) status tended to have simultaneous ERCC1 protein expression (P< 0.001). Stage III CRC patients with deficient MMR (dMMR) had higher prognoses than the same stage patients with pMMR (DFS: 74% vs 65%, P = 0.04; OS: 79% vs 69%, P = 0.04). Here, dMMR is also associated with poorer survival for stage II patients after chemotherapy (DFS: 66% vs 78%, P = 0.04). Stage II and III patients that were shown to express ERCC1 protein had higher DFS and OS than those that were deficient in expression (stage II, DFS: 83% vs 70%, P = 0.006; OS 85% vs 73%, P = 0.02. Stage III, DFS: 67% vs56%, P = 0.03; OS: 71% vs 57%, P = 0.04).ConclusionsOur results indicate that dMMR appeared to predictive of a survival benefit for stage III CRC patients. We also found the determination of ERCC1 expression to be useful for predicting DFS or OS for stage II and III CRC patients. In addition, the expression of MMR genes and ERCC1 showed a significant relationship.

Prognostic Role of ERCC1 Protein Expression and its Correlation with 18F-FDG Uptake on PET in Patients with Resected Non-Small Cell Lung Cancer

Prognostic Role of ERCC1 Protein Expression and its Correlation with 18F-FDG Uptake on PET in Patients with Resected Non-Small Cell Lung Cancer

Prognostic implication of ERCC1 protein expression in resected oropharynx and oral cavity cancer

BackgroundExcision repair cross complement group 1 (ERCC1) expression is a predictive biomarker for platinum-containing treatment in squamous cell carcinoma of head and neck (SCCHN). However, the prognostic significance after surgical resection is not well understood. MethodsOropharynx (n=143) or oral cavity (n=61) SCCHN patients undergoing surgery were included. ERCC1 protein expression and HPV status were assessed by ERCC1 and p16 immunohistochemistry. ResultsThe ERCC1, over-expressed in 66.7% of patients, was associated with oral cavity cancer (P<0.001), well differentiation (P=0.036), and HPV negativity (P<0.001). In TCGA database, ERCC1 mRNA upregulation was enriched in HPV-negative and oral cavity cancers, and associated with HRAS mutation (P<0.001). The prognostic role of ERCC1 was not different according to HPV status. High ERCC1 expression showed a trend toward poor prognosis in patients with an advanced stage (P=0.079) with marginal significance. ConclusionsThe ERCC1 expression was not prognostic in surgically resected oropharynx/oral cavity SCCHN, irrespective of HPV status. However, it could provide additional prognostic information for advanced stage patients.

985P - Prognostic implication of ERCC-1 protein expression in resected head and neck cancer

985P - Prognostic implication of ERCC-1 protein expression in resected head and neck cancer

Lack of Correlation between Aberrant p16, RAR-β2, TIMP3, ERCC1, and BRCA1 Protein Expression and Promoter Methylation in Squamous Cell Carcinoma Accompanying Candida albicans-Induced Inflammation

Hyperplastic candidiasis is characterized by thickening of the mucosal epithelia with Candida albicans infection with occasional progression to squamous cell carcinoma (SCC). C. albicans is a critical factor in tumor development; however, the oncogenic mechanism is unclear. We have previously produced an animal model for hyperplastic candidiasis in the rat forestomach. In the present study, we investigate whether impaired DNA methylation and associated protein expression of tumor suppressor and DNA repair genes are involved in the SCC carcinogenesis process using this hyperplastic candidiasis model. Promoter methylation and protein expression were analyzed by methylation specific PCR and immunohistochemical staining, respectively, of 5 areas in the forestomachs of alloxan-induced diabetic rats with hyperplastic candidiasis: normal squamous epithelia, squamous hyperplasia, squamous hyperplasia adjacent to SCC, squamous hyperplasia transitioning to SCC, and SCC. We observed nuclear p16 overexpression despite increases in p16 gene promoter methylation during the carcinogenic process. TIMP3 and RAR-β2 promoter methylation progressed until the precancerous stage but disappeared upon malignant transformation. In comparison, TIMP3 protein expression was suppressed during carcinogenesis and RAR-β2 expression was attenuated in the cytoplasm but enhanced in nuclei. ERCC1 and BRCA1 promoters were not methylated at any stage; however, their protein expression disappeared beginning at hyperplasia and nuclear protein re-expression in SCC was observed only for ERCC1. These results suggest that aberrant p16, RAR-β2, TIMP3, ERCC1, and BRCA1 expression might occur that is inconsistent with the respective gene promoter methylation status, and that this overexpression might serve to promote the inflammatory carcinogenesis caused by C. albicans infection.

ERCC1 and telomere status in breast tumours treated with neoadjuvant chemotherapy and their association with patient prognosis.

Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy‐number variations) by immunohistochemistry, qRT‐PCR and quantitative multiplex fluorescent‐PCR (QMF‐PCR). A comprehensive analysis of telomere characteristics was performed using qPCR for telomere length and qRT‐PCR for telomerase (hTERT), tankyrase 1 (TNKS) and shelterin complex (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2) gene expression. Short telomeres, high hTERT and TNKS expression and low ERCC1 protein expression were independently associated with worse survival outcome. Interestingly, ERCC1 gains and losses correlated with worse disease‐free (p = 0.026) and overall (p = 0.043) survival as compared to survival of patients with normal gene copy‐numbers. Unsupervised hierarchical clustering of all ERCC1 and telomere parameters identified four subgroups with distinct prognosis. In particular, a cluster combining low ERCC1, ERCC1 gene alterations, dysfunctional telomeres and high hTERT and a cluster with high TNKS and shelterin expression correlated with poor disease‐free (HR= 5.41, p= 0.0044) and overall survival (HR= 6.01, p= 0.0023) irrespective of tumour stage and grade. This comprehensive study demonstrates that telomere dysfunction and DDR can contribute synergistically to tumour progression and chemoresistance. These parameters are predictors of clinical outcome in breast cancer patients treated with NCT and could be useful clinically as prognostic biomarkers to tailor adjuvant chemotherapy post‐NCT.

DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance.

BackgroundSurgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated.Material/MethodsNSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression.ResultsERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05).ConclusionsERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway.

ERCC1, as Prognostic and Predictive Marker in Metastatic Colorectal Cancer Patients Treated with Oxaliplatin based Chemotherapy

Excision repair cross-complementation group 1 gene (ERCC1) encodes an enzymethat is essential for the efficient repair of DNA damage induced by platinum compounds such as Oxaliplatin agent.Our study investigated the association between ERCC1 protein expression and clinical outcomes of metastaticcolorectal cancer (CRC) patients administrated with combination Oxaliplatin (OX) and 5-fluorouracil (5-FU)treatment.

Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer.

Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.