Excision Repair Cross-complementation Group Research Articles

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 >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.

The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma.

The aim of this study was to evaluate the effects of polymorphisms in excision repair cross-complementation group 1 (ERCC1) and alpha-fetoprotein (AFP) genes and their haplotypes on the susceptibility to hepatocellular carcinoma (HCC), and to decipher the association between single-nucleotide polymorphisms (SNPs) and clinicopathologic characteristics of HCC.Peripheral blood DNA was extracted from 206 subjects. SNaPshot technique was used for genotyping 5 SNP sites of the ERCC1 rs735482, rs1046282, rs3212948, and AFP rs737241, rs4024 genotypes. Chi-squared test and logistic regression model were used to analyze the relationship of different genotypes or haplotype and the susceptibility and clinicopathologic characteristics of HCC.The frequency of GG.GA and AA genotypes at the AFP rs737241 site in the case and control groups showed statistically significant differences (P < .05). The risk of HCC in subjects carrying mutated allele A (GA+AA) was increased by 0.543-times (P < .05) compared to that in the subjects with the GG genotype. Significant differences were observed in the linkage disequilibrium between 2 of the five SNPs (P < .05); the frequency of ERCC1 C-C and AFP A-A haplotypes was significantly lower in the case group than in the control group (P < .05). The results of clinicopathologic analysis showed that A allele at the rs737241 locus could increase the expression level of AFP (P = .007), the rs1046282 mutation C allele could increase the AFP expression level (P = .011), rs4024 locus mutation A allele could reduce the risk of vascular invasion (P = .013), rs3212948 locus mutation T allele could reduce the differentiation of liver cancer (P = .022), rs1046282 locus C allele could reduce the DNA load of hepatitis B virus (P = .035), and rs735482 A allele could increase the tumor size in HCC (P = .037).The SNPs in rs737241 for AFP gene may correlate with the occurrence of HCC. The SNPs in ERCC1 and AFP genes may affect the prognosis of HCC, offering reliable information for early prediction of tumor progression and diagnosis of HCC.

The effect of excision repair cross complementing 1 and thymidylate synthetase mRNA expression and uridine-diphosphoglucuronosyl transferase 1A1 gene polymorphism on chemotherapeutic effect and prognosis of gastric cancer

Objective To analyze the impact of excision repair cross complementation group 1 (ERCC1), thymidylate synthetase (TYMS) mRNA expression, and uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28/*6 gene polymorphisms on chemoresponse and clinical outcome of patients with colorectal cancer treated with fluorouracil combined with oxaliplatin (FOLFOX) or fluorouracil combined with irinotecan (FOLFIRI) regimen. Methods Among the 96 patients with gastric cancer, 47 patients were treated with FOLFOX regimen, and 49 patients underwent neoadjuvant chemotherapy with FOLFIRI regimen. The gene expression of gastric cancer patients was analyzed, and the chemotherapy efficacy and prognosis of the two groups were observed. Results Chemotherapy remission rate (72.4%, 57.9%) in patients with low expression of ERCC1 and TYMS, median disease progression time (12.6, 16.9 months), median overall survival time (26.4, 23.8 months, respectively) were significantly better than those in patients with high expression of ERCC1 and TYMS (38.9%, 34.5%) and median disease progression. Time (7.9, 12.3 months respectively) and median total survival (15.7, 16.2 months respectively) were significantly different (P 0.05). In addition, there was no significant difference in the efficacy of chemotherapy between *28 and *6 genotypes (P>0.05). Conclusion The gene expression of gastric cancer patients was analyzed, and the chemotherapy efficacy and prognosis of the two groups were observed. Key words: Colorectal cancer; Excision repair cross complementing 1; Thymidylate synthetase; Uridine-diphosphoglucuronosyl transferase 1A1; Chemoresistence

Beyond DNA repair: the novel immunological potential of PARP inhibitors

ABSTRACTLoss of excision repair cross-complementation group 1 (ERCC1), frequently found in lung cancer, and mutations in breast cancer type 1/2 susceptibility genes (BRCA1/2), often found in ovarian, breast and prostate cancers, confer sensitivity to poly-(ADP-ribose) polymerase inhibitors (PARPi). Our work, and that of others, shows that PARPi selectively trigger tumor cell-autonomous immune phenotypes in ERCC1- or BRCA-defective contexts. This suggests that PARPi, used in appropriately selected populations, might mediate their therapeutic effects by potentiating anti-tumor immunity.

The Potential Application of Spring Sargassum glaucescens Extracts in the Moisture-Retention of Keratinocytes and Dermal Fibroblast Regeneration after UVA-Irradiation

Sargassum glaucescens is a marine brown alga with high antioxidant activity. To evaluate the potential application of Sargassum glaucescens extracts (SGE) in skincare, we performed in vitro assays in dermal fibroblasts and epidermal keratinocytes. The antioxidant activity of SGE was confirmed by the suppression of H2O2-induced reactive oxygen species (ROS) production in dermal fibroblasts and in vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity. In the wound healing assay, application of 2 mg/ml SGE stimulated the wound closure of CCD-966SK fibroblasts by a 2.95-fold in comparison to the control. Furthermore, treatment with SGE of concentrations ranging from 0.25 to 1 mg/ml promoted CCD-966SK cell regeneration after UVA irradiation. At the molecular level, 1 mg/ml SGE induced expressions of anti-oxidative genes SOD1 (Superoxide dismutase 1) and GPX1 (Glutathione peroxidase 1), and DNA repair regulatory genes XRCC1 (X-ray repair cross-complementing protein 1) and ERCC6 (Excision repair cross-complementation Group 6) in CCD-966SK cells after UVA irradiation. Therefore, SGE displayed beneficial effects on cell regeneration and the protection of dermal cells against UVA irradiation. In epidermal cells, SGE stimulated the cell proliferation of human primary epidermal keratinocytes. Application of 0.03125 mg/ml SGE induced the expressions of skin barrier-related genes TGM1 (Transglutaminase 1), KRT10 (Keratin 10) and KRT14 in keratinocytes. Meanwhile, SGE induced the gene expression of FLG (Filaggrin), which promoted the production of natural moisturizing factor (NMF) for maintaining the moisture and barrier functions of skin.

Excision repair cross-complementing group-1 (ERCC1) gene induction in peripheral blood mononuclear cells as a marker of outcome in patients with colorectal cancer treated with oxaliplatin.

542 Background: Oxaliplatin is a third generation platinum agent that confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the standard of care regimens for patients with colorectal cancer (CRC). Tissue resistance to oxaliplatin appears to be multifactorial, with the nucleotide excision repair (NER) pathway playing a major role. We have previously demonstrated that Excision Repair Cross-Complementing group-1 (ERCC1), can be induced in colorectal cell lines on exposure to Oxaliplatin and high levels confer resistance to apoptosis. We aim to further this knowledge by analyzing gene expression in vivo, using PBMC as a surrogate, to assess ERCC1 as a biomarker of sensitivity to Oxaliplatin therapy. Methods: Patients with CRC who received oxaliplatin were consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC. Results: Fifty-four patients were enrolled on study, 25 (46.3%) had mCRC. Twenty-four patients were included in final analysis based on clinical data. Thirteen (52%) had an increase in ERCC expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. However, in these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with Oxaliplatin. This induction can serve as a potential marker of resistance to oxaliplatin based chemotherapy in mCRC as evidenced by the significant difference in PFS. Further analyses of the influence of ERCC1 polymorphisms on outcomes is underway.

Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma.

There are several DNA repair pathways that protect cellular DNA from injury, such as nucleotide excision repair (NER) and mismatch repair (MMR). The protein product of the excision repair cross-complementation group 1 (ERCC1) gene plays a pivotal role in NER. The exact relationship between MMR proteins and ERCC1 is not well known in colorectal carcinoma (CRC). To investigate expression of ERCC1 and MMR proteins in colorectal mucinous carcinoma (MA) and non-mucinous carcinoma (NMA) using tissue microarray technique. We studied tumor tissue specimens from 150 patients with colorectal mucinous (MA) and non-mucinous adenocarcinoma (NMA). Tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for ERCC1, MLH1, MSH2, MSH6, and PMS2. NMA showed a significantly more frequent aberrant cytoplasmic expression than MA while MA showed a more frequent intact nuclear expression than NMA. There were no significant differences between the NMA and MA groups in the expression of MMR proteins. In NMA cases, ERCC1 expression was significantly related to MMR status while was not significantly related in MA cases. ERCC1 expression was not significantly related to overall and disease-free survival in both NMA and MA groups. this study is the first to investigate the relation between MMR status and ERCC1 expression in colorectal MA and NMA. ERCC1 expression was significantly related to MMR status only in NMA cases. Hence, the current study emphasizes that further research about the relation between various DNA repair pathways is needed.

Study of the Relationship between ERCC1 Polymorphisms and Response to Platinum-based Chemotherapy in Iranian Patients with Colorectal and Gastric Cancers.

This study was designed to evaluate the effect of excision repair cross complementing group 1 (ERCC1) rs11615 codon 118C/T gene polymorphisms on treatment outcomes in Iranian patients receiving oxaliplatin-based regimens for colorectal (CRC) and gastric cancers (GC). Patients, who were candidates to receive oxaliplatin-based chemotherapy, entered into the study. In 2-week intervals, the patients received combination regimen of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) for 3 months. ERCC1 rs11615 codon 118C/T polymorphism was tested by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method using patients’ peripheral blood lymphocytes. The tumor response to chemotherapy was evaluated by examining the size of the tumor using CT scan. Association between response rates, according to the RECIST criteria, and patients’ genotypes was evaluated. Any relationship between response rate and possible explanatory factors was also determined. Overall, 40 patients (13 females (32.5%), and 27 males (67.5%)) enrolled in the study. Four patients (10.0%) carried the homo­zygous mutation (T/T genotype), ten patients (25.0%) were heterozygous (C/T genotype), and twenty-six patients (65%) were homo­zygous (C/C genotype). Response rate were 30.77%, 20.00%, and 0.00% for the genotypes C/C, C/T, and T/T, respectively. No significant association between response rate and genotypes was observed (p = 0.64). Patients with well- and moderately-differentiated histological grade of the tumor showed a better response rate (100.00% of 2 patients and 66.66% of 12 patients, respectively) compared to those with poorly differentiated (0.00% of 26 patients) histological grade (p < 0.001). Further multicenter studies are recommended to confirm conclusively our findings.

Is excision repair cross-complementation Group1 expression a biological marker in nasopharynx carcinoma?

To determine the prognostic value of excision repairs cross-complementation group1 (ERCC1) gene in cases with nasopharyngeal carcinoma (NPC) treated with platinum-containing chemotherapy (PCT). The present study was included 33 cases in local advanced stage with NPC. ERCC1 expression was evaluated by using immunohistochemical staining in biopsy specimens. We evaluated the relationship between the degree of ERCC1 expression and clinicopathological features, response to therapy, survival rates in cases with NPC, retrospectively. ERCC1 expression was not observed in 5 (15.15%) of all cases. Thirteen (39.9%) cases weakly positive (+1, +2) and 15 (45.5%) cases of all them were rather strongly positive (+3). There was no statistically significant difference between the degree of ERCC1 expression and clinicopathological features, response to treatment, survival rates (P > 0.05) in cases with NPC. ERCC1 expression has no predictive value for survival in cases locally advanced stage with NPC. Evaluation of ERCC1 expression is not appropriate with a biomarker to detect cases who can benefit from PCT in NPC.

Germline polymorphisms (SNPs) to predict toxicity and efficacy in FLOT-treated patients with locally advanced gastroesophageal junction or gastric adenocarcinoma—data from the NeoFLOT study

Background: Perioperative treatment is standard of care in Western Europe for locally advanced gastroesophageal cancer (GEC) [gastric and gastroesophageal junction (GEJ) adenocarcinoma]. Predictive markers for toxicity and efficacy prior to start with chemotherapy are desirable, particularly when applying a prolonged neoadjuvant treatment. Here we analyse the impact of previously published SNPs involved in drug metabolism and DNA repair. Methods: Genomic DNA was isolated from 48 tumor samples of patients treated within the NeoFLOT-study. In this trial, FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) was administered every two weeks for 6 cycles chemotherapy prior to surgery. Direct DNA sequencing was carried out for rs25487 [Excision Repair Cross-Complementation Group 1 (XRCC1)], rs1805087 [5-methyltetrahydrofolate-homocysteine methyltransferase (MTR)], rs11615 and rs3212986 (both ERCC1), rs1799793 and rs13181 (both ERCC2), rs1801019 [Orotate Phosphoribosyl Transferase (OPRT)] and rs16430del [thymidylate synthase: 6-bp-deletion in the in the 3' untranslated regulatory region (TS3utrdel)]. Furthermore, thymidylate synthase: 28-bp-tandem repeats in the 5' untranslated region (TS5utr tandem repeat) polymorphism was analysed by Restriction Fragment Length Polymorphism (RFLA). Toxicity was stated according to NCI-CTC version 4.0. For efficacy analysis overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and recurrence-free survival (RFS) were used. Results: ERCC2 rs1799793 was significantly associated with thrombocytopenia ≥ grade 3 (P=0.04) and overall hematotoxicity ≥ grade 3 (P=0.04) while rs13181 was significantly associated with leukopenia ≥ grade 3 (P=0.03). Rs11615 of ERCC1 had a predictive value for leukopenia (P=0.04) and thrombocytopenia (P=0.008). Rs1805087 of MTR and TS5utr tandem repeat polymorphism were both associated with anemia (P=0.04 and 0.04, respectively). Concerning non-hematological toxicity, rs1805087 of MTR was associated with diarrhea (P=0.004). Regarding treatment efficacy, patients harbouring the minor allele of C of OPRT rs1801019 obtained a higher ORR and showed a better but statically non-significant prolonged PFS and OS while rs3212986 of ERCC1 was associated with pCR rate (P=0.006). Conclusions: For single nucleotide polymorphism (SNPs) of ERCC1/2, MTR and TS tandem repeat we could demonstrate the predictive value for toxicity of FLOT in GEC. Furthermore, OPRT rs1801019 might be useful to predict response for neoadjuvant treatment.

TGF beta promotes repair of bulky DNA damage through increased ERCC1/XPF and ERCC1/XPA interaction.

Transforming growth factor beta (TGFβ) is multifunctional cytokine that is involved in the coordination and regulation of many cellular homeostatic processes. Compromised TGFβ activity has been attributed to promotion of human cancers. Recent studies have identified a role for TGFβ in response to radiation-induced DNA damage, suggesting a link between TGFβ and the DNA damage response with implications for cancer development. In this study, the effects of TGFβ on promoting the repair of bulky DNA damage, through modulation of nucleotide excision repair (NER), were investigated. We show that treatment of cells with exogenous TGFβ leads to enhanced repair of DNA damage formed by polycyclic aromatic hydrocarbons and ultraviolet-C radiation; similarly, cells with constitutively activated endogenous TGFβ signaling show comparable responses. This effect of TGFβ is independent of the cell cycle. The response to TGFβ is decreased in cells that have compromised TGFβ signaling through RNA interference of Smad4 and is decreased in NER-deficient cells and cells with compromised NER through RNA interference of excision repair cross-complementing group 1 (ERCC1). Increased interaction and nuclear localization of ERCC1/xeroderma pigmentosum (XP) F and ERCC1/XPA proteins is observed after TGFβ treatment. Our study represents the first experimental evidence of a role for TGFβ in the repair of bulky DNA damage resulting from promotion of the interaction and localization of repair protein complexes involved in the incision step of NER.

Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells.

The 5′-3′ structure-specific endonuclease ERCC1/XPF (Excision Repair Cross-Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors.

PO534 Cost-Effectiveness Analysis of Therapeutic Hypothermia In Critical Patient After Cardiac Arrest: Estimate of Lifetime Horizon Follow-Up

Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC.We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (−37C/A and −524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at −37 and two C alleles at −524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin + gemcitabine, cisplatin + docetaxel, gemcitabine + docetaxel; docetaxel + vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population.42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47–72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15–26) and OS was 40.4 weeks (95% CI = 32–55). Treatment was well tolerated.We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.

Immunohistochemistry Biomarkers Predict Survival in Stage II/III Gastric Cancer Patients: From a Prospective Clinical Trial.

PurposeIdentification of biomarkers to predict recurrence risk is essential to improve adjuvant treatment strategies in stage II/III gastric cancer patients. This study evaluated biomarkers for predicting survival after surgical resection.Materials and MethodsThis post-hoc analysis evaluated patients from the CLASSIC trial who underwent D2 gastrectomywith orwithout adjuvant chemotherapy (capecitabine plus oxaliplatin) at the Yonsei Cancer Center. Tumor expressions of thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and programmed death-ligand 1 (PD-L1) were evaluated by immunohistochemical (IHC) staining to determine their predictive values.ResultsAmong 139 patients, IHC analysis revealed high tumor expression of TS (n=22, 15.8%), ERCC1 (n=23, 16.5%), and PD-L1 (n=42, 30.2%) in the subset of patients. Among all patients, high TS expression tended to predict poor disease-free survival (DFS; hazard ratio [HR], 1.80; p=0.053), whereas PD-L1 positivity was associated with favorable DFS (HR, 0.33; p=0.001) and overall survival (OS; HR, 0.38; p=0.009) in multivariate Cox analysis. In the subgroup analysis, poor DFS was independently predicted by high TS expression (HR, 2.51; p=0.022) in the adjuvant chemotherapy subgroup (n=66). High PD-L1 expression was associated with favorable DFS (HR, 0.25; p=0.011) and OS (HR, 0.22; p=0.015) only in the surgery-alone subgroup (n=73). The prognostic impact of high ERCC1 expression was not significant in the multivariate Cox analysis.ConclusionThis study shows that high TS expression is a predictive factor for worse outcomes on capecitabine plus oxaliplatin adjuvant chemotherapy, whereas PD-L1 expression is a favorable prognostic factor in locally advanced gastric cancer patients.

Prognostic role of beclin-1 in locally advanced non-small cell lung cancer in patients receiving docetaxel-platinum induction chemotherapy.

Background/AimsThe outcome of local treatment for advanced non-small cell lung cancer (NSCLC) remains poor, with therapies such as induction chemotherapy (IC) yielding conflicting results. This study aimed to assess the clinicopathologic and prognostic significance of the excision repair cross-complementation group 1 (ERCC1), beclin-1, and glucose-regulated protein of molecular mass 78 (GRP78) in patients with locally advanced NSCLC receiving docetaxel-platinum IC, along with efficacy and safety.MethodsThis is a retrospective observational cohort study. We reviewed medical records of 31 NSCLC patients receiving docetaxel-platinum IC, and conducted immunohistochemical staining of ERCC1, beclin-1, and GRP78.ResultsResponse rate was 67.8% with 10.7 months of median relapse-free survival (RFS) and 23.1 months of median overall survival (OS), and no treatment-related death was reported. High expression of ERCC1, beclin-1, and GRP78 was identified in 67.7%, 87.1%, and 67.7%, respectively. Expression of ERCC1 and GRP78 did not reveal statistical significance in survival, whereas high beclin-1 expression revealed longer OS (7.6 months vs. 23.2 months; log-rank p = 0.024). In multivariate analysis, histologic differentiation (hazard ratio [HR], 3.48; p < 0.001), stage (HR, 8.5; p = 0.024), and adjuvant treatment (HR, 16.1; p = 0.001) were related to RFS, and in OS, stage (HR, 5.4; p = 0.037), adjuvant treatment (HR, 8.6; p = 0.004), and beclin-1 expression (HR, 8.2; p = 0.011) were identified as significant prognostic factors.ConclusionsOur findings suggest that high beclin-1 expression predicts longer survival in locally advanced NSCLC and docetaxel-platinum IC is a treatment option that deserves consideration.

Contribution of excision repair cross-complementing group 1 genotypes to triple negative breast cancer risk.

Compared with other subgroups of breast cancer, triple negative breast cancer (TNBC) is considered to be the one with the greatest invasiveness and metastatic mobility, and the highest recurrence rate. Considering the lack of predictive markers for TNBC, we aimed to examine the contribution of excision repair cross complementing-group 1 (ERCC1) genotypes to TNBC. The rs11615 and rs3212986 of ERCC1 were investigated and evaluated for their associations with susceptibility to breast cancer, especially TNBC, in Taiwan. In this study, 1,232 breast cancer patients (104 were TNBC) and 1,232 healthy controls were recruited and their genotypes at ERCC1 rs11615 and rs3212986 were revealed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Our results indicated that genotypes of ERCC1 rs11615 (Ptrend = 2.2*10E-9), but not rs3212986 (Ptrend = 0.6181), were associated with breast cancer risk. In the allelic frequency distribution analysis, breast cancer patients carried the T allele of ERCC1 rs11615 a higher rate than the control subjects, further supporting the idea that ERCC1 rs11615 TT genotype is positively associated with breast cancer susceptibility. More importantly, the frequency of the ERCC1 rs11615 TT genotype was even higher among TNBC patients than among other subtypes of breast cancer patients (P = 0.0001, odds ratio = 1.73, 95% confidence interval = 1.15–2.63). The genotypes of ERCC1 rs11615 were not associated with Ki67 status. Our findings firstly show that the T allele of ERCC1 rs11615 can serve as a predictive biomarker for breast cancer and TNBC. We believe that ERCC1 could serve as a target for personalized treatment of breast cancer, especially for TNBC.

Excision repair cross-complementing group 1 (ERCC1) overexpression inhibits cell apoptosis and is associated with unfavorable prognosis of esophageal squamous cell carcinoma.

Excision repair cross-complementing group 1 (ERCC1) functions as a nucleotide excision repair (NER) enzyme. Altered ERCC1 expression or function is closely associated with cancer development and progression. This study determined the association of ERCC1 expression with survivin expression, clinicopathological characteristics, and survival of esophageal squamous cell carcinoma (ESCC) patients after postoperative concurrent chemoradiotherapy.Tissue specimens from 102 resected ESCC patients were acquired for immunohistochemical analysis of ERCC1 and survivin protein expression.ERCC1 expression was detected in 62.7% of ESCC tissues and in 9.8% of normal squamous epithelium tissues (P < .01), while survivin expression was detected in 60.8% of ESCC tissues and in 19.6% of normal squamous epithelia (P < .01). ERCC1 overexpression associated with advanced tumor clinical stage and lymph node metastasis (P < .05), but not with tumor size, depth of invasion, or differentiation (P > .05). ERCC1 overexpression was also associated with survivin levels (r = 0.42, P < .01) and worse progression-free survival of ESCC patients after concurrent chemoradiotherapy. Multivariate analysis data revealed that ERCC1 and survivin protein expression were independent predictors of overall survival of ESCC patients after chemotherapy and/or radiotherapy (P < .05).ERCC1 overexpression is an important phenotype that is associated with ESCC lymph node metastasis and advanced tumor clinical stages. ERCC1 expression may also inhibit ESCC cell apoptosis via regulating survivin expression, and ERCC1 and survivin overexpression are independent predictors of prognosis for ESCC patients who receive chemotherapy and/or radiotherapy.

Predictive value of excision repair cross-complementing group 2 gene Lys751Gln and Asp312Asn polymorphisms in melanoma risk.

Epidemiological studies have assessed the association between excision repair cross-complementing group 2 (ERCC2) Lys751Gln and Asp312Asn polymorphisms and melanoma risk with conflicting results. Relevant articles were searched from PubMed, Embase, and Web of Science with a time limit of 3 September 2016. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. We performed this meta-analysis with 12 studies including 6157 cases and 8873 controls for Lys751Gln and nine studies including 5037 cases and 7542 controls for Asp312Asn polymorphism. Overall, no significant associations were found under all the models for Lys751Gln polymorphism, and significant associations were found for Asp312Asn polymorphism for AA versus GG (OR=1.12, 95% CI=1.00-1.26) and for the recessive model (OR=1.11, 95% CI=1.00-1.24). In the stratification analyses by source of control: for Lys751Gln polymorphism, significant associations were found for CC versus AA (OR=1.19, 95% CI=1.04-1.36) and the recessive model (OR=1.15, 95% CI=1.02-1.30); for Asp312Asn polymorphism, significant associations were found for AA versus GG (OR=1.31, 95% CI=1.11-1.53) and the recessive model (OR=1.29, 95% CI=1.11-1.50). This meta-analysis suggested that both the Lys751Gln and Asp312Asn polymorphisms were risk factors for melanoma risk in population-based subgroup.

Excision repair cross-complementing group 1 (ERCC1) overexpression inhibits cell apoptosis and is associated with unfavorable prognosis of esophageal squamous cell carcinoma: Erratum.

Excision repair cross-complementing group 1 (ERCC1) overexpression inhibits cell apoptosis and is associated with unfavorable prognosis of esophageal squamous cell carcinoma: Erratum.

Unexpected Growth-Promoting Effect of Oxaliplatin in Excision Repair Cross-Complementation Group 1 Transfected Human Colon Cancer Cells

The nucleotide excision repair protein excision repair cross-complementation group 1 (ERCC1) has been repeatedly shown to be involved in the sensitivity of cancer cells to platinum derivatives. In order to better understand this process, we transfected HCT-116 cells with a plasmid encoding ERCC1 and studied their in vitro and in vivo behaviour. No main differences were observed for sensitivity to platinum drugs, DNA repair capacity and clonogenicity in vitro. However, ­ERCC1-transfected HCT-116 cells showed paradoxical behaviour in vivo with increased growth in mice treated with oxaliplatin as compared to untreated mice. The Trop2 protein was identified as being potentially involved in the underlying mechanism for these observations, as it was overexpressed in transfected cells. Our results suggest complex regulation of signalling in cancer cells exposed to cancer drugs.