ERCC1

Gene Summary

Gene:ERCC1; ERCC excision repair 1, endonuclease non-catalytic subunit
Aliases: UV20, COFS4, RAD10
Location:19q13.32
Summary:The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA excision repair protein ERCC-1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: ERCC1 (cancer-related)

Cao Y, Zhang G, Wang P, et al.
Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer.
BMC Gastroenterol. 2017; 17(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Individualized therapeutic regimen is a recently intensively pursued approach for targeting diseases, in which the search for biomarkers was considered the first and most important. Thus, the goal of this study was to investigate whether the UGT1A1, ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A genes are underlying biomarkers for gastric cancer, which, to our knowledge, has not been performed.
METHODS: Ninety-eight tissue specimens were collected from gastric cancer patients between May 2012 and March 2015. A multiplex branched DNA liquidchip technology was used for measuring the mRNA expressions of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A. Direct sequencing was performed for determination of UGT1A1 polymorphisms. Furthermore, correlations between gene expressions, polymorphisms and clinicopathological characteristics were investigated.
RESULTS: The expressions of TYMS, TUBB3 and STMN1 were significantly associated with the clinicopathological characteristics of age, gender and family history of gastric cancer, but not with differentiation, growth patterns, metastasis and TNM staging in patients with gastric cancer. No clinical characteristics were correlated with the expressions of ERCC1, BRCA1, RRM1 and TOP2A. Additionally, patients carrying G allele at -211 of UGT1A1 were predisposed to developing tubular adenocarcinoma, while individuals carrying 6TAA or G allele respectively at *28 or -3156 of UGT1A1 tended to have a local invasion.
CONCLUSIONS: The UGT1A1 polymorphism may be useful to screen the risk population of gastric cancer, while TYMS, TUBB3 and STMN1 may be potential biomarkers for prognosis and chemotherapy guidance.

Tsuji D, Ikeda M, Yamamoto K, et al.
Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.
Medicine (Baltimore). 2016; 95(44):e5151 [PubMed] Related Publications
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.

Bahamon BN, Gao F, Danaee H
Development and Validation of an ERCC1 Immunohistochemistry Assay for Solid Tumors.
Arch Pathol Lab Med. 2016; 140(12):1397-1403 [PubMed] Related Publications
CONTEXT: - Excision repair cross-complementation 1 (ERCC1) is a key enzyme in nuclear excision repair pathway and has a critical role in helping remove DNA adducts caused by cross-linking agents, such as platinum-containing cancer chemotherapies and other DNA-damaging therapeutic modalities. ERCC1 expression, evaluated by techniques such as immunohistochemistry, has been associated with clinical response; ERCC1(+) tumors are more resistant to cisplatin treatment than are ERCC1(-) tumors. Although several immunohistochemistry, anti-ERCC1 antibodies are available, the 8F1 clone, in particular, has been used in many studies. Recent evidence has suggested that the 8F1 antibody cross-reacts with at least one other protein, raising concerns about the specificity of this clone.
OBJECTIVE: - To design an immunohistochemistry assay to detect ERCC1 levels that show dynamic range and consistent analytic performance.
DESIGN: - Two different primary antibodies to ERCC1, clones 4F9 and D6G6, were evaluated on formalin-fixed, paraffin-embedded tissue. We then performed a fit-for-purpose assay validation with the 4F9 clone, which included sensitivity assessment across several solid tumor types and evaluation of analytic parameters, such as precision and reproducibility.
RESULTS: - The 4F9 clone was consistently superior to the D6G6 clone in the optimization phase. A range of expression was seen in ovarian, head and neck, non-small cell lung, and esophageal cancer samples when tested with the 4F9 clone. The antibody showed acceptable reproducibility (31.02%) and precision (16.06%).
CONCLUSIONS: - This assay can be used to assess ERCC1 levels during clinical studies of patient tumors from a variety of tumor types.

Chen P, Li J, Chen YC, et al.
The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells.
Cell Oncol (Dordr). 2016; 39(6):511-522 [PubMed] Related Publications
PURPOSE: Cisplatin can cause a variety of DNA crosslink lesions including intra-strand and inter-strand crosslinks (ICLs), which are associated with the sensitivity of cancer cells to cisplatin. Here, we aimed to assess the contribution of the Fanconi anemia (FA), homologous recombination (HR) and nucleotide excision repair (NER) pathways to cisplatin resistance in non-small cell lung cancer (NSCLC)-derived cells.
METHODS: The expression of FA, HR and NER pathway-associated genes was assessed by RT-qPCR and Western blotting. siRNAs were used to knock down the expression of these genes. CCK-8 and flow cytometry assays were used to assess the viability and apoptotic rate of NSCLC-derived cells, respectively. Immunofluorescence and alkaline comet assays were used to assess the repair of ICLs.
RESULTS: We found that acquired cisplatin-resistant NSCLC-derived A549/DR cells exhibited markedly enhanced FA and HR repair pathway capacities compared to its parental A549 cells and another independent NSCLC-derived cell line, Calu-1, which possesses a moderate innate resistance to cisplatin. siRNA-mediated silencing of the FA-associated genes FANCL and RAD18 and the HR-associated genes BRCA1 and BRCA2 significantly potentiated the sensitivity of A549/DR cells to cisplatin compared to A549 and Calu-1 cells, suggesting that the acquired cisplatin resistance in A549/DR cells may be attributed to enhanced FA and HR pathway capacities responsible for ICL repair. Although we found that expression knockdown of the NER-associated genes XPA and ERCC1 sensitized the three NSCLC-derived cell lines to cisplatin, the sensitization effect was more significant in Calu-1 cells than in A549 and A549/DR cells, implying that the innate cisplatin resistance in Calu-1 cells may result from an increased NER activity.
CONCLUSIONS: Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC.

Zheng DL, Tang GD, Chen YN, et al.
Genetic variability of ERCC1 and ERCC2 genes involved in the nucleotide excision repair pathway influences the treatment outcome of gastric cancer.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
We conducted a prospective study to investigate whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. Between January 2010 and December 2012, 246 patients with pathologically proven gastric cancer who were receiving platinum-based chemotherapy were recruited from the First Affiliated Hospital of Guangxi Medical University. The genotyping of the gene polymorphisms was conducted using the polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that the AA genotype of ERCC1 rs3212986 was associated with lower rates of complete remission and partial remission following chemotherapy in gastric cancer patients, and the OR (95%CI) was 0.19 (0.06-0.60). We found that the AA genotype of rs3212986 was correlated with higher risk of death from gastric cancer according to the Cox proportional hazards model, and the adjusted HR (95%CI) was 1.60 (0.81-3.16). However, we found no association between ERCC1 rs11615, ERCC2 rs13181, and ERCC2 rs1799793 and overall survival of gastric cancer. In conclusion, the results of the present retrospective study indicate that the ERCC1 rs3212986 gene polymorphism has a significant effect on the pharmacokinetics and treatment outcome of gastric cancer.

Tonissi F, Lattanzio L, Astesana V, et al.
Reoxygenation Reverses Hypoxia-related Radioresistance in Head and Neck Cancer Cell Lines.
Anticancer Res. 2016; 36(5):2211-5 [PubMed] Related Publications
BACKGROUND/AIM: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells.
MATERIALS AND METHODS: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied.
RESULTS: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment.
CONCLUSION: Reoxygenation before RT rescued radiosensitivity in HNC cells.

Li F, Xie X, Ren X, Zhang J
A meta-analysis identifies ERCC1 gene polymorphism as a predictor of better patient response to treatment with radiochemotherapy.
Cancer Chemother Pharmacol. 2016; 77(6):1183-91 [PubMed] Related Publications
PURPOSE: This meta-analysis aimed to evaluate whether an association exists between the ERCC1 rs11615 (C>T) polymorphism and patient response to platinum-based chemotherapy and radiation-based chemotherapy.
METHODS: Publications were selected from PubMed and MEDLINE. A meta-analysis was conducted to determine the association between genetic polymorphisms and response to platinum-based chemotherapy and radiation-based chemotherapy by checking the odds ratios (ORs) and 95 % confidence intervals (CIs).
RESULTS: In our overall analysis, the ERCC1 rs11615 (C>T) polymorphism was not associated with response to platinum-based chemotherapy in five comparison models. In the subgroup analyses by ethnicity, the ERCC1 rs11615 (C>T) polymorphism was shown to be significantly associated with objective response in Caucasian patients treated with platinum-based chemotherapy in the recessive model (TT vs.
CT/CC: OR 0.696, 95 % CI 0.508-0.954, heterogeneity = 0.330), but the association was not observed in the Asian population. The C allele was significantly associated with better response to radiochemotherapy in the recessive model comparison (TT vs.
CC/CT: OR 0.724, 95 % CI 0.585-0.869, heterogeneity = 0.008). Subgroup analysis by cancer type revealed that the C allele of ERCC1 rs11615 predicted a better response in esophageal cancers in two comparison models (T vs. C: OR 0.756, 95 % CI 0.648-0.880, heterogeneity = 0.653; TT vs.
TC/CC: OR 0.457, 95 % CI 0.306-0.684, heterogeneity = 0.723). Stratified analysis by ethnicity showed a better response in Caucasians in allelic comparison model (T vs. C: OR 0.895, 95 % CI 0.819-0.977, heterogeneity = 0.095).
CONCLUSION: Together, our results suggest that the ERCC1 rs11615 (C>T) polymorphism was associated with therapeutic response in Caucasian patients and C allele of ERCC1 rs11615 could represent a genetic molecular marker to predict better patient response to radiochemotherapy in recessive model. However, larger prospective randomized trials will be required.

Smid D, Kulda V, Srbecka K, et al.
Tissue microRNAs as predictive markers for gastric cancer patients undergoing palliative chemotherapy.
Int J Oncol. 2016; 48(6):2693-703 [PubMed] Related Publications
MicroRNAs have the potential to become valuable predictive markers for gastric cancer. Samples of biopsy tissue, routinely taken from gastric cancer patients undergoing palliative chemotherapy, constitute suitable material for microRNA profiling with the aim of predicting the effect of chemotherapy. Our study group consisted of 54 patients, all of whom underwent palliative chemotherapy based on 5-fluorouracil (5-FU) or 5-FU in combination with platinum derivatives between 2000 and 2013. The expression of 29 selected microRNAs and genes BRCA1, ERCC1, RRM1 and TS, in gastric cancer tissue macrodissected from FFPE tissue samples, was measured by quantitative RT-PCR. The relationship between gene expression levels and time to progression (TTP) and overall survival (OS) was analysed. From the set of the 29 microRNAs of interest, we found high expression of miR-150, miR-342-3p, miR-181b, miR-221, miR-224 and low levels of miR-520h relate to shorter TTP. High levels of miR-150, miR-192, miR-224, miR-375 and miR-342-3p related to shorter OS. In routinely available FFPE tissue samples, we found 6 miRNAs with a relation to TTP, which may serve as predictors of the effectiveness of palliative treatment in gastric cancer patients. These miRNAs could also help in deciding whether to indicate palliative chemotherapy.

Liu K, Jiang Y
Polymorphisms in DNA Repair Gene and Susceptibility to Glioma: A Systematic Review and Meta-Analysis Based on 33 Studies with 15 SNPs in 9 Genes.
Cell Mol Neurobiol. 2017; 37(2):263-274 [PubMed] Related Publications
At present, many publications have evaluated the correlation between the DNA repair gene polymorphisms and glioma susceptibility. However, the results remain inconclusive. The aim of this research is to exhaustively assess the association of genetic polymorphisms in DNA repair genes with glioma risk in human. Meta-analysis method was conducted, and 33 studies with 15 SNPs in 9 genes were included (12553 glioma cases and 17178 controls). Correlation strength was evaluated by odds ratio with a 95 % confidence interval. Rs1799782 T allele and rs25487A allele might bring about higher risk of glioma in Asian population. Rs1805377 G allele was an increased risk genetic factor of glioma. Asian carried with rs3212986 A allele was more likely to have glioma. Rs1800067 G allele was a risk factor of developing glioma. Carriers with rs12917 CC genotype in MGMT gene had higher risk of glioma in Caucasian than other non-CC genotype carriers. Carriers with rs1136410 T allele in PARP1 gene could more likely to develop glioma in Caucasian. This meta-analysis suggests that glioma susceptibility is associated with rs1799782 and rs25487 of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), rs1805377 of XRCC4, rs1800067 of excision repair cross-complementing rodent repair deficiency complementation group 4 (ERCC4) and rs3212986 of ERCC1 in Asian population, and rs12917 of O-6-methylguanine-DNA methyltransferase (MGMT) and rs1136410 of poly(ADP-ribose) polymerase 1 (PARP1) in Caucasian population.

He MG, Zheng K, Tan D, Wang ZX
Association between ERCC1 and ERCC2 gene polymorphisms and susceptibility to pancreatic cancer.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
We conducted a study to investigate the association between ERCC1 (rs3212986) and ERCC2 (rs13181) gene polymorphisms and the risk of pancreatic cancer in a Chinese population. A total of 217 pancreatic cancer patients and 244 control subjects were recruited from the Nuclear Industry 215 Hospital of Shaanxi Province between February 2013 and December 2014. Genomic DNA was extracted from peripheral blood samples using a TIANamp Blood DNA Kit (Tiangen, Beijing, China) according to the manufacturer's instructions. The ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length of polymorphism. Unconditional logistic regression analyses showed that subjects with the CC genotype of ERCC1 rs3212986 were susceptible to the development of pancreatic cancer when compared with subjects with the AA genotype (OR = 2.57, 95%CI = 1.34-5.02). The ERCC1 rs3212986 gene polymorphism was associated with increased risk of pancreatic cancer in the dominant (OR = 1.54, 95%CI = 1.05-2.28) and recessive (OR = 2.22, 95%CI = 1.20-4.19) models. However, no significant difference was found between the ERCC2 rs13181 polymorphism and the risk of pancreatic cancer in the codominant, dominant, and recessive models. We suggest that the ERCC1 rs3212986 polymorphism increases susceptibility to pancreatic cancer in the codominant, dominant, and recessive models, although further studies are needed to confirm our findings.

Ying MF, Zhao R
Role of single nucleotide polymorphisms of DNA repair genes in susceptibility to pancreatic cancer in Chinese population.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
We conducted a case-control study to investigate the role of ERCC1-ERCC5 gene polymorphisms in the risk of pancreatic cancer. This study included 195 patients who were newly diagnosed with histopathologically confirmed primary pancreatic cancer, and 254 controls were recruited from Sir Run Run Shaw Hospital, between January 2012 and December 2014. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Unconditional logistic regression analyses showed that the TT genotype of ERCC1 rs3212986 was associated with an increased risk of pancreatic cancer, and the OR (95%CI) was 2.26 (1.21-4.22). However, we did not find a significant association between ERCC1 rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, and ERCC5 rs2094258 polymorphisms and risk of pancreatic cancer. In summary, we found that the presence of the ERCC1 rs3212986 polymorphism correlated with an increased risk of pancreatic cancer.

Mokmeli S, Tehrani GA, Zamiri RE, Bahrami T
Investigating the Frequency of the ERCC1 Gene C8092A Polymorphism in Iranian Patients with Advanced Gastric Cancer Receiving Platinum-based Chemotherapy.
Asian Pac J Cancer Prev. 2016; 17(3):1369-72 [PubMed] Related Publications
BACKGROUND: Platinum compounds are the main drugs for treatment of advanced gastric cancer. Previous studies have shown that clinical outcome with platinum-based compounds depends on ERCC1 polymorphisms. The aim of this study was to investigate the frequency of a common polymorphism of ERCC1 gene (C8092A) in Iranian patients with advanced gastric cancer receiving platinum chemotherapy.
MATERIALS AND METHODS: Genetic analysis of the ERCC1 C8092A polymorphism was performed by the PCR - RFLP method using 50 paraffin-embedded tissue specimens.
RESULTS: Of the 50 cases, 32% of individuals showed CC genotype, 24% of them had CA genotype and 44% of patients had AA genotype.
CONCLUSIONS: Based on the results, using of platinum-based chemotherapy would be expected to be specifically beneficial in only 32% of patients.

Zhao R, Ying MF
Association between ERCC1 and ERCC2 polymorphisms and breast cancer risk in a Chinese population.
Genet Mol Res. 2016; 15(1):15017263 [PubMed] Related Publications
We conducted a case-control study to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 gene polymorphisms in the development of breast cancer. Between March 2012 and March 2014, a total of 242 newly diagnosed breast cancer patients with histopathologically confirmed primary breast cancer and 242 healthy controls were recruited. Genotyping of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism analysis. Unconditional logistic regression analyses indicated that the TT genotype of rs3212986 was associated with a higher risk of breast cancer compared to that associated with the GG genotype (OR = 2.05, 95%CI = 1.13-3.78). In dominant and recessive models, we found that the rs3212986 polymorphism was associated with increased risk of breast cancer, and the ORs were 1.50 (95%CI = 1.03-2.18) and 1.74 (95%CI = 1.01-3.11), respectively. In summary, we found that the ERCC1 rs3212986 polymorphism was associated with the development of breast cancer.

Wang XC, Wang F, Quan QQ
Roles of XRCC1/XPD/ERCC1 Polymorphisms in Predicting Prognosis of Hepatocellular Carcinoma in Patients Receiving Transcatheter Arterial Chemoembolization.
Genet Test Mol Biomarkers. 2016; 20(4):176-84 [PubMed] Related Publications
OBJECTIVE: To investigate the potential prognostic roles of polymorphisms in the X-ray repair cross-complementing group 1 (XPCC1), xeroderma pigmentosum group D (XPD) and excision repair cross-complementing group 1 (ERCC1) genes for patients with hepatocellular carcinoma (HCC) receiving transcatheter arterial chemoembolization (TACE).
METHODS: Clinical data and blood samples from 308 HCC patients receiving TACE were collected between January 2010 and December 2013. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP) analyses was used to determine the genotypes of the XPCC1 (rs25487), XPD (rs13181) and ERCC1 (rs11615) genes. The relationships between the genotypes and the efficacy of TACE treatment were analyzed.
RESULTS: The XRCCI rs25487 polymorphism was associated with a favorable prognosis in HCC patients receiving TACE (p = 0.006), and patients carrying variant genotypes (A/A + G/A) were associated with significantly reduced risk of death compared with those with the wild genotype (G/G) (HR = 0.556; 95% CI = 0.354-0.874). These findings were supported by Kaplan-Meier survival curve analysis showing that median survival time for patients with A/A + G/A genotypes was significantly longer compared with those with the G/G genotype (11.2 month vs. 8.0 months; log rank p = 0.006). Stratified analyses revealed that A/A + G/A genotypes of XRCC1 rs25487 are associated with significantly reduced risk of death compared with the G/G genotype in patients grouped by tumor size, portal vein tumor thrombus (PVTT), alpha-fetoprotein (AFP) and TNM stage (all p < 0.05). The ERCC1 rs13181 and XPD rs11615 polymorphisms were not predictive of clinical outcome for HCC patients receiving TACE (both p > 0.05).
CONCLUSION: The XRCC1 rs25487 polymorphisms are prognostic for HCC patients receiving TACE. The ERCC1 and XPD polymorphisms had no relationship to the clinical outcomes.

Polat G, Yılmaz U, Anar C, et al.
Is there relationship between excision repair cross-complementation 1 expression level and response to treatment and prognosis in an advanced stage lung cancer treated with cisplatin-based chemotherapy?
Indian J Cancer. 2015 Jul-Sep; 52(3):277-80 [PubMed] Related Publications
AIM: It is important to know the tumor resistance against cisplatin before the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the response to treatment and survival in patients with NSCLC treated with cisplatin-based chemotherapy according to excision repair cross-complementation 1 (ERCC1) expression.
MATERIALS AND METHODS: Among 119 patients treated with cisplatin and vinorelbine or docetaxel, 39 (32%) patients enrolled who have enough tumor tissue to analyze ERCC1 expression. ERCC1 expression defined as negative in score 0-1, positive in score 2-3.
RESULTS: There was no difference between ERCC1 positive and negative groups (P = 0.63). Mean survival was 14.7 months (95% confidence interval [CI]; 10.0-19.3 month) in ERCC1 negative group, 10.9 months (95% CI; 7.4-14.3 month) in ERCC1 positive group (P = 0.23). Progression free survival was 7.9 months in ERCC1 negative group (95% CI; 5.8-9.9 months), 6.2 months in ERCC1 positive group (95% CI; 4.0-8.5 months) (P = 0.27).
CONCLUSION: Identification of ERCC1 expression level of tumor tissues in NSCLC patients before treatment was not useful in prediction of treatment response and prognosis.

Zhang Q, Sun T, Kang P, et al.
Combined analysis of rearrangement of ALK, ROS1, somatic mutation of EGFR, KRAS, BRAF, PIK3CA, and mRNA expression of ERCC1, TYMS, RRM1, TUBB3, EGFR in patients with non-small cell lung cancer and their clinical significance.
Cancer Chemother Pharmacol. 2016; 77(3):583-93 [PubMed] Related Publications
PURPOSE: The assessment of single gene such as ERCC1, TYMS, RRM1, TUBB3, EGFR, KRAS, BRAF, PIK3CA, ALK, and ROS1 is now widely applied in therapeutic decisions of non-small cell lung cancer (NSCLC). The aim of our study was to concurrently analyze these genes and evaluate their clinical significance in patients with NSCLC.
METHODS: Rearrangement of ALK and ROS1 was analyzed in 120 patients using FISH assays. Somatic mutation of EGFR, KRAS, BRAF, PIK3CA and mRNA expression of ERCC1, TYMS, RRM1, TUBB3, EGFR were examined by liquidchip platform in 350 patients . Data on clinical features were obtained from medical records of 119 patients, and the follow-up was conducted in 106 patients who received platinum-based adjuvant chemotherapy.
RESULTS: We identified 5.0% ALK rearrangements, 1.7% ROS1 rearrangements, 36.6% EGFR mutations, 8.9% KRAS mutations, 0% BRAF mutations, and 4.0% PIK3CA mutations. Double or coexisting mutations were identified in 13 patients. Significant correlations were observed among EGFR, KRAS mutation, ERCC1, TYMS, RRM1, TUBB3, EGFR expression, and clinical features, especially histology (P < 0.05). Significant cross-correlations were observed in some pairs of genes (P < 0.05). Patients with low RRM1 expression had a better progression-free survival (PFS) (P < 0.05). Furthermore, EGFR-mutated patients with low RRM1 expression or patients with both ERCC1 and RRM1 low expression had a better PFS (P < 0.05).
CONCLUSION: Combined analysis of these commonly studied genes may promote the individual treatment in NSCLC. RRM1 may be a prognostic and predictive biomarker for PFS in patients with NSCLC who received platinum-based adjuvant chemotherapy, and combining EGFR mutation and RRM1 expression or combining ERCC1 and RRM1 expression can enhance prognostic and predictive power for PFS.

Mo J, Luo M, Cui J, Zhou S
Prognostic value of ERCC1 and ERCC2 gene polymorphisms in patients with gastric cancer receiving platinum-based chemotherapy.
Int J Clin Exp Pathol. 2015; 8(11):15065-71 [PubMed] Free Access to Full Article Related Publications
We conducted a prospective study to analyze whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. A total of 228 patients with pathologically proven gastric cancer and receiving platinum-based chemotherapy were recruited from our hospital between October 2009 and October 2011. The ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 polymorphisms were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Conditional logistic regression analysis revealed that patients carrying the CA and AA genotypes of ERCC1 rs3212986 polymorphism showed a poorer response to chemotherapy compared to the CC genotype (CA vs. CC: OR = 0.28, 95% CI = 0.06-0.98, P = 0.04; AA vs. CC: OR = 0.49, 95% CI = 0.06-0.98, P = 0.01). Moreover, the CA+AA genotype of ERCC1 rs3212986 polymorphism showed a significantly poorer response to chemotherapy (CA+AA vs. CC: OR = 0.49, 95% CI = 0.27-0.90). Patients with the AA genotype of ERCC1 rs3212986 polymorphism had a longer overall survival time when compared with the CC genotype (34.91 months vs. 51.19 months, log-rank P = 0.003). The AA genotype of ERCC1 rs3212986 polymorphism in gastric cancer patients was correlated with a higher risk of death from varying causes by the Cox proportional hazards model, compared to the CC genotype (HR = 6.19, 95% CI = 1.42-30.60). In conclusion, the ERCC1 rs3212986 polymorphism was found to influence the response to chemotherapy and overall survival of gastric cancer patients.

Heo SJ, Jung I, Lee CK, et al.
A randomized phase II trial of ERCC1 and RRM1 mRNA expression-based chemotherapy versus docetaxel/carboplatin in advanced non-small cell lung cancer.
Cancer Chemother Pharmacol. 2016; 77(3):539-48 [PubMed] Related Publications
OBJECTIVES: To evaluate whether the selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients.
MATERIALS AND METHODS: Eligible patients were randomly assigned 1:1 to the experimental and control arms; the experimental arm received gemcitabine/carboplatin (GC) if ERCC1 and RRM1 expression was low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received DC.
RESULTS: This study was prematurely terminated after the futility analysis of 43 progression-free survival (PFS) events. A total of 55 patients (n = 26 in the experimental arm, n = 29 in the control arm) were evaluable for efficacy and toxicity. Nineteen (73.1%) patients were assigned to receive GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to DV in the experimental arm. The overall response rates were 42.3 and 48.3% in the experimental and control arms, respectively, which were not statistically different (P = 0.657). The median PFS was 5.2 months in the experimental arm and 5.4 months in the control arm (P = 0.286). The median overall survival was 17.4 months in the experimental arm and 12.6 months in the control arm (P = 0.638). The occurrence of grade 3 or higher neutropenia (69.2 vs. 93.1%, P = 0.035) and febrile neutropenia (3.8 vs. 24.1%, P = 0.054) was more common in the control arm.
CONCLUSION: ERCC1 and RRM1 mRNA expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

Meng ZJ, Tao K
Enhancement of Chemosensitivity by Stathmin-1 Silencing in Gastric Cancer Cells In Situ and In Vivo.
Oncol Res. 2016; 23(1-2):35-41 [PubMed] Related Publications
Reports show that the stathmin gene may have a close relationship with tumor chemotherapeutic sensitivity. However, the effect of stathmin-1 on the chemosensitivity of gastric cancer to docetaxel has not been clearly determined. siRNA targeting stathmin-1 was introduced. The cell growth inhibition, expression of associated proteins, cell cycle, and apoptosis were evaluated by MTT, Western blot, and flow cytometric assays, respectively. The influence of silencing stathmin-1 was detected in situ and in vivo. SGC7901/docetaxel cells are the drug-resistant cells. After silencing stathmin-1, the resistance index (RI) reduced to 3.41, the expressions of STMN-1, MDR1, and ERCC1 were downregulated, but caspase 3 was upregulated. Stathmin-1 siRNA could improve the chemosensitivity of gastric cancer cells to docetaxel, making the percentage of cells at the sub-G1 stage increase and promote apoptosis. The growth of transplantation tumor was significantly suppressed. Therefore, stathmin-1 might be a potential target for enhancing the chemosensitivity of gastric cancer.

Rumiato E, Boldrin E, Malacrida S, et al.
A germline predictive signature of response to platinum chemotherapy in esophageal cancer.
Transl Res. 2016; 171:29-37.e1 [PubMed] Related Publications
Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management.

Mian M, McNamara MG, Doherty M, et al.
Predictive and prognostic values of ERCC1 and XRCC1 in biliary tract cancers.
J Clin Pathol. 2016; 69(8):695-701 [PubMed] Related Publications
AIMS: To investigate the predictive and prognostic values of DNA repair genes excision repair cross-complementation group 1 (ERCC1) and X-ray repair cross-complementing group 1 (XRCC1) in tumour samples from patients with a diagnosis of biliary tract cancer (BTC).
METHODS: Expressions of ERCC1 and XRCC1 were determined by immunohistochemistry (IHC) for 160 patients with BTC and association with clinicopathological features and patient survival was performed to evaluate their predictive and prognostic values.
RESULTS: Neoplastic tissue showed much lower nuclear expression compared with non-neoplastic tissue for ERCC1 (median immunostaining score (IS)=0.7 (95% CI 0.2 to 1.3) vs 8.0 (95% CI 5.5 to 8.0), p<0.001) and XRCC1 (median IS=4.0 (95% CI 3.0 to 5.5) vs 8.0 (95% CI 8.0 to 12.0), p<0.001). High nuclear expression of both proteins was able to predict better overall survival (OS) in patients with gallbladder adenocarcinoma, distal bile duct and perihilar cholangiocarcinoma undergoing gemcitabine as adjuvant therapy (ERCC1: median OS estimate=39.7 vs 22.9 months, p=0.011; XRCC1: median OS estimate=33.8 vs 14.6 months, p=0.005). Intense cytoplasmic expression of XRCC1 was found in 12 patients; these patients had significantly more frequent lymph node metastasis (90.0% vs 48.1%, p=0.017) and worse OS (median estimate=12.6 months vs 25.6 months, p=0.004) and recurrence-free survival (median estimate=5.7 months vs 15.1 months, p=0.011). Vascular invasion was significantly more frequent in patients with low nuclear expression for ERCC1 (58.7% vs 20.9%, p<0.001) and XRCC1 (69.6% vs 30.3%, p=0.001).
CONCLUSIONS: IHC expression of ERCC1 and XRCC1 has some predictive and prognostic values in patients with BTC. Nuclear expression of ERCC1 and XRCC1 may be used to predict therapeutic response in patients undergoing gemcitabine monotherapy.

Bai Y, Wang L, Li G, et al.
Genetic variability of ERCC1 genes in NER pathway influences the treatment outcome of gastric cancer.
Int J Clin Exp Pathol. 2015; 8(10):13367-73 [PubMed] Free Access to Full Article Related Publications
We conducted a prospective study to analyze whether six SNPs in ERCC1 gene could serve as potential biomarkers for prognosis of gastric cancer. Between January 2010 and December 2012, 270 patients with pathologically proven gastric cancer and receiving platinum-based chemotherapy were recruited in our study. Genotyping of the ERCC1 rs11615, rs2298881, rs3212955, rs3212961, rs3212986 and rs735482 were carried out using the Sequenom MassARRAY platform. By logistic regression analysis, patients carrying the GT and TT genotypes of rs3212986 showed a significantly poorer response to chemotherapy than did those carrying the GG genotype, and the ORs (95% CI) were 0.47 (0.25-0.88) and 0.18 (0.08-0.41), respectively. By Cox proportional hazards models, the GT and TT genotypes of rs3212986 were correlated with increased risk of death when compared with the GG genotype, and the adjusted HRs (95% CIs) were 1.79 (1.01-3.16) and 2.57 (1.18-5.62), respectively. However, we did not find significant association between ERCC1 rs11615, rs2298881, rs3212955, rs3212961 and rs735482 and response to chemotherapy and overall survival in patients with gastric cancer. In conclusion, the results of the present retrospective study indicate that there is a significant difference in biological behavior between ERCC1 rs3212986 gene polymorphism and treatment outcome of gastric cancer.

Zhong G, Li HK, Shan T, Zhang N
Genetic variability of DNA repair mechanisms in chemotherapy treatment outcome of gastric cancer patients.
Genet Mol Res. 2015; 14(4):17228-34 [PubMed] Related Publications
We investigate whether three common polymorphisms in ERCC1 and ERCC2 are predictor factors for the chemotherapy response, as well as the clinic outcome of patients with gastric cancer. Between May 2011 and May 2013, 263 patients with gastric cancer who were newly diagnosed by histopathology were enrolled in our study. Genotyping of the ERCC1 rs11615 and rs3212986, and ERCC2 rs1799793 polymorphisms were conducted by the polymerase chain reaction-restriction fragment length polymorphism assay. Patients carrying the TT genotype and TT+CT genotype of ERCC1 rs11615 were associated with poorer response to chemotherapy and shorter survival times when compared with the CC genotype. In conclusion, our results suggested that the ERCC1 rs11615 polymorphism in the DNA repair pathways can be used as predictive factors to the clinical outcome of patients with gastric cancer.

Shimamoto Y, Nukatsuka M, Takechi T, Fukushima M
Association between mRNA expression of chemotherapy-related genes and clinicopathological features in colorectal cancer: A large-scale population analysis.
Int J Mol Med. 2016; 37(2):319-28 [PubMed] Free Access to Full Article Related Publications
To establish the individualized treatment of patients with colorectal cancer, factors associated with chemotherapeutic effects should be identified. However, to the best of our knowledge, few studies are available on this topic, although it is known that the prognosis of patients and sensitivity to chemotherapy depend on the location of the tumor and that the tumor location is important for individualized treatment. In this study, primary tumors obtained from 1,129 patients with colorectal cancer were used to measure the mRNA expression levels of the following genes associated with the effects of standard chemotherapy for colorectal cancer: 5-fluorouracil (5-FU)-related thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP); folate-related dihydrofolate reductase (DHFR), folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH); irinotecan-related topoisomerase I (TOP1); oxaliplatin-related excision repair cross-complementing 1 (ERCC1); biologic agent-related vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Large-scale population analysis was performed to determine the association of gene expression with the clinicopathological features, in particular, the location of the colorectal cancer. From the results of our analysis of the mRNA expression of these 10 genes, we noted the strongest correlation between DPYD and TYMP, followed by TYMS and DHFR. The location of the colorectal cancer was classified into 4 regions (the right‑ and left-sided colon, rectosigmoid and rectum) and was compared with gene expression. A significant difference in all genes, apart from VEGF, was noted. Of the remaining 9 genes, the highest expression of TYMS and DPYD was observed in the right‑sided colon; the highest expression of GGH and EGFR was noted in the left-sided colon; the highest expression of DHFR, FPGS, TOP1 and ERCC1 was noted in the rectosigmoid, whereas TYMP expression was approximately equivalent in the right-sided colon and rectum, and higher than that in other locations. The data generated from this study may prove to be useful for the development of individualized chemotherapeutic treatments for patients with colorectal cancer, and will mean that the tumor location is taken into account.

Lin S, Lei K, Du W, et al.
Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism.
Int J Biochem Cell Biol. 2016; 71:24-34 [PubMed] Related Publications
The resistance to oxaliplatin (L-OHP) is a major obstacle to ideal therapeutic outcomes in colorectal cancer. Photodynamic therapy (PDT) induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a well-studied photosensitizer. In this study, we explored the role of hypericin-mediated PDT (HY-PDT) in sensitizing human colorectal cancer cells towards L-OHP. Pre-treatment with HY-PDT enhanced the anti-tumor activity of L-OHP via decreasing drug efflux and increasing platinum accumulation. Further research showed that HY-PDT-mediated resensitization of resistance cells towards L-OHP was dependent on regulation of MRP-2, instead of p-gp. HY-PDT was also found to inhibit intracellular glutathione (GSH) and Glutathione S-transferase (GST), suggesting the involvement of GSH-related detoxification in the sensitization effect. Additionally, enhanced DNA double-strand breaks (DSBs) was observed following HY-PDT/L-OHP combined treatment. HY-PDT lowered the removing rate of platinum from DNA and down-regulated the expression of ERCC1 and XPF, two critical enzymes involved in nucleotide excision repair (NER) pathway. GSH monoethyl ester (GSH-EE) antagonized HY-PDT-induced ROS and repressed sensitization to platinum. Taken together, HY-PDT mediated sensitization of L-OHP in human colorectal cancer is mediated by ROS, whose mechanism involves affecting drug efflux, GSH-related detoxification and NER-mediated DNA repair.

Grossi F, Dal Bello MG, Salvi S, et al.
Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer.
Dis Markers. 2015; 2015:302649 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and q
RT-PCR: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients.

Zhang YY, Gu KS, Wu HY, et al.
Correlation of ERCC1 expression in peripheral blood lymphocytes with outcomes of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy.
Genet Mol Res. 2015; 14(4):15921-9 [PubMed] Related Publications
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.

Sun Y, Tan L, Li H, et al.
Association of NER pathway gene polymorphisms with susceptibility to laryngeal cancer in a Chinese population.
Int J Clin Exp Pathol. 2015; 8(9):11615-21 [PubMed] Free Access to Full Article Related Publications
We systematically analyzed the association of nine SNPs of seven key NER pathway genes with the development of laryngeal cancer patients, and investigated whether NER pathway polymorphisms could serve as potential biomarkers for laryngeal cancer risk. 271 patients with pathologically proven laryngeal cancer and 271 control subjects were included in our study. Genotyping of ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs50871, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs2094258, XPA rs2808668 and XPC rs2228001 were analyzed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying the TT genotype of ERCC1 rs11615 were correlated with an increased risk of larynx cancer when compared with the CC genotype (OR=1.89, 95% CI=1.07-3.37; P value=0.02). Moreover, individuals with the GG genotype of ERCC2 rs50871 were associated with an elevated risk of larynx cancer when compare with the TT genotype (OR=2.03, 95% CI=1.15-3.63; P value=0.01). We found a significant interaction between ERCC2 rs50871 polymorphism and tobacco smoking in the risk of larynx cancer (P for interaction <0.05). In conclusion, our study showed that ERCC1 rs11615 and ERCC2 rs50871 polymorphisms could influence the risk of larynx cancer in Chinese population, particularly among smokers.

Zhao F, Shang Y, Zeng C, et al.
Association of single nucleotide polymorphisms of DNA repair genes in NER pathway and susceptibility to pancreatic cancer.
Int J Clin Exp Pathol. 2015; 8(9):11579-86 [PubMed] Free Access to Full Article Related Publications
In our study, we conducted a case-control study to investigate the association of ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC and DDB2 gene polymorphisms in the risk of pancreatic cancer. Between May 2012 and May 2014, a total of 246 patients with who were newly diagnosed with histopathologically confirmed primary pancreatic cancer and 246 controls were selected into our study. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs873601, XPA rs2808668, XPC rs2228000, XPC rs2228001 and DDB2 rs2029298 were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying with TT genotype of ERCC1 rs3212986 and GG genotype of ERCC2 rs13181 were associated with increased risk of pancreatic cancer when compared with wide-type genotype, and the adjusted ORs (95% CI) were 2.40 (1.29-4.52) and 2.27 (1.26-4.15), respectively. We found that individuals carrying with GT+TT genotype of ERCC1 rs3212986 and TG+GG genotype of ERCC2 rs1318 gene polymorphisms were correlated with higher risk of pancreatic cancer in smokers when compared with non-smokers, and the adjusted ORs (95% CI) were 1.89 (1.05-3.40) and 1.88 (1.06-3.34), respectively. In conclusion, our study suggests that ERCC1 rs3212986 and ERCC2 rs1318 gene polymorphisms contribute to the development of pancreatic cancer, especially in smokers.

El-Deiry WS, Vijayvergia N, Xiu J, et al.
Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites.
Cancer Biol Ther. 2015; 16(12):1726-37 [PubMed] Free Access to Full Article Related Publications
Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n = 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p = 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p = 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n = 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.

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