ERCC1 Polymorphisms Research Articles

ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer.

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.

Genotyping, in silico screening and molecular dynamics simulation of SNPs of MGMT and ERCC1 gene in lung cancer patients treated with platinum-based doublet chemotherapy

Lung cancer, the leading cause of death worldwide, arises from an intricate combination of genetic and environmental factors. Genetic variations can influence the chemotherapeutic response of lung cancer patients in DNA repair genes. This study examines the response to platinum-based drugs among lung cancer patients of North Indian descent who possess genetic variations in the MGMT and ERCC1 genes. P CR-RFLP method was used for genotypic analysis. MedCalc statistical software was used to calculate odds ratios and Median Survival Time (MST). GROMACS software was used to perform Molecular dynamic simulation. ADCC Patients revealed a significant association with MGMT in the heterozygous genotype (HR= 1.56, p=0.02) and also with ERCC1 in both mutant and combined variants (HR= 1.25, p=0.01; HR=0.78, p=0.03). SQCC subjects harbouring ERCC1 polymorphism also reported a 2-fold increase in hazard ratio and a corresponding decrease in survival time for heterozygous and combined variants (HR= 2.55, p=0.02; HR 2.33, p=0.01, respectively). MD simulation results demonstrate a lower RMSD, stable radius of gyration, and lower RMSF, indicating the mutated MGMT protein is more stable than the wild. Further, the docking score for DNA-Wild and DNA-L84F mutants are -201.6 and -131.8, respectively. MD Simulation of the complexes further validated the results. Our study concludes that MGMT and ERCC1 polymorphisms are associated with decreased overall survival. Further, computational analysis of MGMT (rs12917) polymorphism revealed that mutated MGMT cannot bind properly to the DNA and hence cannot properly repair DNA, resulting in lower overall survival. Communicated by Ramaswamy H. Sarma

ERCC1 and MGMT Methylation as a Predictive Marker of Relapse and FOLFOX Response in Colorectal Cancer Patients from South Tunisia.

Genetic and epigenetic modifications present a major cause of relapse and treatment failure in colorectal cancer. This study aims to appreciate the prognostic and predictive value of ERRC1 and MGMT methylation. We also studied the prognostic impact of the ERCC1 rs11615 polymorphism as well as its expression. Methylation profiles of ERCC1 and MGMT were tested by methylation-specific PCR. A polymorphism of ERCC1 was studied using PCR-RFLP and its expression was examined by immunohistochemistry. ERCC1 was methylated in 44.6% of colorectal adenocarcinoma while MGMT was methylated in 69% of cases. MGMT methylation was strongly associated with lymph node metastasis, lymph invasion, venous invasion, perineural invasion, distant metastasis and relapse. Patients with methylation of both genes were more likely to have a poor prognosis and display chemoresistance. IHC analysis revealed that ERCC1 staining was noted in 52.8% of colorectal adenocarcinoma and inversely related to distant metastasis and cancer recurrence. Kaplan Meier analysis revealed that the worst overall survival was significantly associated with ERCC1 and MGMT methylation while decreased ERCC1 expression and T/T genotype exhibited the best overall survival. The methylation of MGMT, alone or combined with ERCC1, is predictive for poor prognosis, short overall survival and chemotherapy response in colorectal cancer.

Abstract P4-01-31: High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms

Abstract CDK4/6 inhibitors (CDK4/6i) is well established as the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC), in combination with endocrine therapy. CDK4/6i extend a chemotherapy-free, progression free survival (PFS) that preserves quality of life in patients. The most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect, especially for palbociclib and ribociclib. In PALOMA-2 and MONALEESA-2, where neutropenia was prevalent (any grade neutropenia 79.5%, grade 3/4 neutropenia 66.5% in PALOMA-2, and any grade neutropenia: 74.3%, grade 3/4 55.3% in MONALEESA-2), although febrile neutropenia seldom occurred (1.8%). Several studies have proposed different genetic factors predisposing to CDK4/6 inhibitor induced neutropenia, including Duffy antigen polymorphisms, ABCB1 and ERCC1 polymorphisms (ABCB1_rs1128503, ABCB1_rs1045642, ERCC1_rs11615, ERCC1_rs3212986), CDK6 polymorphisms, and others. Subgroup studies from the PALOMA trials have suggested that Asian patients receiving palbociclib have higher rates of neutropenia, although the exact explanation is unknown. We conducted a retrospective analysis of 102 Taiwanese patients who received palbociclib for HR(+) mBC at the Taipei Veterans General Hospital for the clinical features, incidence and time course of neutropenia were analyzed. Significant neutropenia incidence was observed (> 95% of all grade neutropenia, 74.5% grade 3/4 neutropenia). In addition, in our clinical cohort, one of the patients was a long term peritoneal dialysis patient newly diagnosed of HR(+) mBC and started on Palbociclib, initially 125mg, later decreased dosage to 100mg after neutropenia occurrence. By Liquid chromatography–mass spectrometry (LC–MS), we quantified the levels of palbociclib in her serum and peritoneal fluid at various time points, while on different dosage use. To our knowledge, this is the first pharmacokinetics analysis on a peritoneal dialysis patient receiving CDK4/6i. To investigate a possible genetic association for the high prevalence of neutropenia, we queried the Taiwan biobank, a nationwide biospecimen repository with 129,586 healthy individual genome wide DNA sequencing data deposited. We investigated the prevalence of the 4 SNPs previously reported to be related to neutropenia in the PALOMA studies. By comparing the Taiwan biobank data to SNP databases from different ethnicities, we observed interesting findings on ethnicity differences of SNP distribution and higher prevalence of neutropenia SNPs. Collectively, in this study we report real world data, biobank genome wide analysis, and a novel report of pharmacokinetic study in a peritoneal dialysis patient, providing novel insights into the real world use of palbociclib and CDKi. Table 1. Median TTF of each subsequent therapy after PAL+ET Characteristics of the clinical cohort treated with palbociclib at TVGH Citation Format: Kuan-Jung Huang, Ting-Hao Kuo, Ta-Chung Chao, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Cheng-Chih Richard Hsu, Jiun-I Lai. High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-31.

ERCC1 polymorphism and its expression associated with ischemic stroke in Chinese population.

Excision repair cross-complementing group 1 (ERCC1) was considered a potential candidate gene for ischemic stroke, and its polymorphisms might be associated with the susceptibility to ischemic stroke. A total of 513 patients with ischemic stroke and 550 control subjects were recruited. The expression levels of ERCC1 messenger RNA (mRNA) in peripheral blood mononuclear cells and its protein in plasma were detected by quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Rs3212986 polymorphism of ERCC1 was detected by PCR-restriction fragment length polymorphism (RFLP-PCR) and was confirmed by sequencing. The association between the ERCC1 rs3212986 polymorphism or its expression and ischemic stroke was further analyzed. The ERCC1 mRNA level in patients with ischemic stroke was lower than that in the control group (P < 0.05). However, the ERCC1 protein level in patients with ischemic stroke was higher than that in the control group (P < 0.05). The A allele of rs3212986 was associated with increased ischemic stroke risk (OR = 1.287, 95% CI = 1.076-1.540, P = 0.006). The association between rs3212986 polymorphism and ischemic stroke susceptibility was found in both recessive (OR = 2.638, 95% CI = 1.744-3.989, P < 0.001) and additive models (OR = 1.309, 95% CI = 1.028-1.667, P = 0.031), respectively. Similar results were obtained in the recessive model (OR = 2.015, 95% CI = 1.087-3.704, P = 0.026) after adjusting for demographic information and other variables. Additionally, the level of ERCC1 mRNA in the CC/CA genotype was higher than that in the AA genotype (P < 0.05). It was suggested that the ERCC1 rs3212986 polymorphism was associated with ischemic stroke susceptibility in a Chinese Han population and that an A allele of rs3212986 was related to increased ischemic stroke risk. The altered ERCC1 expression level caused by the rs3212986 polymorphism might participate in the pathophysiological process of ischemic stroke.

No evidence of relationship between colorectal cancer susceptibility and ERCC2 gene polymorphisms

Background: Excision repair cross-complementing group 2 gene (ERCC2) polymorphisms have been linked as being a risk factor for colorectal cancer (CRC) emergence. However, data from several studies are contradictory. To validate genetic biomarkers of the CRC; the impact of the following ERCC2 polymorphism (rs1799793 and rs238406) was examined on CRC susceptibility among sample of Iraqi population. Methods: A total of 126 subjects were enrolled in this case control study; 78 CRC patients and 48 apparently healthy individuals who are age, gender, smoking status and BMI matched. Polymerase chain reaction (PCR) was used for genotyping, followed by sequencing then the association between genetic polymorphisms and CRC risk was investigated. Results: No associations were detected between ERCC2 genotypes or haplotypes and CRC susceptibility. Even though there was strong linkage disequilibrium (D′= 0.82). After stratification according to participants’ demographics, no effects were observed for age, gender, smoking status and BMI. Conclusions: Taken together the following results suggest that ERCC2 polymorphisms do not influence CRC development.

Genetics of Breast Cancer Among Moroccan Women: a Literature Review

Introduction: Breast cancer (BC) is a heterogeneous disease defined by the accumulation of various molecular alterations that accord each tumor a specific phenotype. Our study aimed to summarize all studies conducted on genetic alterations associated with BC in Moroccan women. Methods: We systematically searched literature databases from the time of inception until 31 August 2021 to collect information concerning the mutation spectrum for BC in Morocco. Results: We identified twenty-three studies including 1858 cases. According to our literature search, twenty-nine mutations were detected in 92/468 (19, 66%) patients for BRCA1/BRCA2 genes. We captured eighteen mutations dispersed in the exons 2, 3, 5, 11, 16, 17, 18, and 20 of the BRCA1 gene (c.68_69delAG, c.116G&gt;A, c.181T&gt;G, c.798_799delTT, c.3279delC, c.2805delA, c.1016dupA, c.2126insA, c.3453delT, c.2884C&gt;T, c.2596C&gt;T, c.2612C&gt;T, c.1186A&gt;G, c. 1100A&gt;G, c.4942A&gt;T, c.5062-5064delGTT, c.5095C&gt;T and c.5309G&gt;T). Moreover, eleven mutations dispersed in the exons 3, 10, 11, and 14 and intron 6 of the BRCA2 gene were detected (c.289G&gt;T, c.1310_1313delAAGA, c.3381delT, c.5073dupA, c.5116_5119delAATA, c.6322C&gt;T, c.3847_3848delGT, c.5576-5579delTTAA, c.7110delA, c.7235inG and c.517-1G&gt;A). A few case-control studies have focused on the association of polymorphisms (SNPs) with the genetic susceptibility of developing BC in Moroccan cases in other genes. A significant association between MTHFR 677T allele ( OR: 2.49, 95% CI: 1.17–5.29, p?=?0.017), TP53 72Pro variant (OR 2.2, 95% CI 1.07-4.54, p = 0.03), CYP2D6*3variant (OR=2.08, CI 1.28-3.39, p=0.003) and the risk of developing BC was observed. Additionally, the rs1799793 ERCC2 polymorphism, four SNPs in APOBEC3B, and one SNP in APOBEC3A were significantly associated with BC risk (p?0.05). Conclusion: This review will allow updating the Moroccan Human Mutation Database. However, large studies including more mutations and polymorphisms are required to determine the prevalence of these mutations in the Moroccan population. This could be very beneficial to guide specific and more effective therapeutic strategies in our country. Keywords: Breast cancer, BRCA1, BRCA2, genetic alterations, Morocco.

Gene polymorphisms and post‐treatment toxicity and treatment response in head and neck squamous cell carcinoma: A scoping review

AbstractVariations in toxicity and treatment response are observed among patients with head and neck squamous cell carcinomas (HNSCCs) despite similar clinicopathologic characteristics that are attributed to gene polymorphisms. This study aimed to review the literatures about the impact of gene polymorphisms on post‐treatment toxicity and treatment response in HNSCCs. A systematic search of all original articles about impact of gene polymorphisms on toxicity and response rate in HNSCCs was done till September 2021 using Google Scholar and PubMed databases. Of 15 345 initial searched articles, 25 articles were finally found to be eligible for inclusion in this review. A total of 41 genes and 69 polymorphisms were examined in these studies. Twenty‐nine genes with 42 polymorphisms for treatment response and 21 genes with 33 polymorphisms were examined for post‐treatment toxicity. Because each of the Asp312Asn ERCC2, IIe105Val GSTP1, and Phe31Ile AurkA polymorphisms has been associated with significant results in two studies, these polymorphisms are more likely to be associated with a treatment response. In the same way, the R521K EGFR polymorphism is more likely to be associated with a post‐treatment toxicity. Because some polymorphisms such as R521K EGFR, *4 or *6 CYP2D6, and rs396991 FcγRIIIa have been associated with significant results in one study (without contradictory study), it is likely that they will be associated with a treatment response by further studies. Due to the paucity of studies, definitive conclusions are impossible, so further studies with meta‐analysis in the future are recommended.

Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients.

The purposes of this study were to identify physiological and genetic factors that contributed to variability of pemetrexed (PEM) exposure and to optimize the dosing regimens for Chinese non-small cell lung carcinoma patients. A prospective population pharmacokinetics (PPK) research was performed in this population. The PEM concentrations of 192 plasma samples from 116 in-hospital patients were detected. All patients were genotyped for polymorphisms. The PPK model of PEM was developed. The pharmacokinetic behavior of PEM was described by a two-compartment model with first-order elimination. The population typical values were as follows: clearance (CL) 8.29 L/h, intercompartmental clearance (Q) 0.10 L/h, central volume of distribution (V1) 18.94 L and peripheral volume of distribution (V2) 5.12 L. Creatinine clearance (CrCl) was identified as a covariate to CL, and ERCC1 (rs3212986) and CYP3A5 (rs776746) gene polymorphisms as covariates to Q. By using empirical body surface area (BSA)-based dosing strategy, PEM exposure decreased with the elevation of CrCl. Contrarily, CrCl-based dosing strategy exhibited a satisfactory efficacy of achieving the target PEM exposure. BSA-based dosing regimen in current clinic practice is not suitable to achieve the target exposure in PEM chemotherapy of Chinese NSCLC patients. Alternatively, renal function-based dosing strategy is suggested.

Modification Effect of PARP4 and ERCC1 Gene Polymorphisms on the Relationship between Particulate Matter Exposure and Fasting Glucose Level.

Particulate matter (PM) has been linked to adverse health outcomes, including insulin resistance (IR). To evaluate the relationships between exposures to PM10, PM2.5–10, and PM2.5; the serum level of fasting glucose, a key IR indicator; and effects of polymorphisms of two repair genes (PARP4 and ERCC1) on these relations, PMs exposure data and blood samples for glucose measurement and genotyping were collected from 527 Korean elders. Daily average levels of PMs during 8 days, from 7 days before examination to the health examination day (from lag day 7 to lag day 0), were used for association analyses, and mean concentrations of PM10, PM2.5–10, and PM2.5 during the study period were 43.4 µg/m3, 19.9 µg/m3, and 23.6 µg/m3, respectively. All three PMs on lag day 4 (mean, 44.5 µg/m3 for PM10, 19.9 µg/m3 for PM2.5–10, and 24.3 µg/m3 for PM2.5) were most strongly associated with an increase in glucose level (percent change by inter-quartile range-change of PM: (β) = 1.4 and p = 0.0023 for PM10; β = 3.0 and p = 0.0010 for PM2.5–10; and β = 2.0 and p = 0.0134 for PM2.5). In particular, elders with PARP4 G-C-G or ERCC1 T-C haplotype were susceptible to PMs exposure in relation to glucose levels (PARP4 G-C-G: β = 2.6 and p = 0.0006 for PM10, β = 3.5 and p = 0.0009 for PM2.5–10, and β = 1.6 and p = 0.0020 for PM2.5; ERCC1 T-C: β = 2.2 and p = 0.0016 for PM10, β = 3.5 and p = 0.0003 for PM2.5–10, and β = 1.2 and p = 0.0158 for PM2.5). Our results indicated that genetic polymorphisms of PARP4 and ERCC1 could modify the relationship between PMs exposure and fasting glucose level in the elderly.

Association of genetic polymorphisms in DNA repair genes ERCC2 Asp312Asn (rs1799793), ERCC2 Lys 751 Gln (rs13181), XRCC1 Arg399 Gln (rs25487) and XRCC3 Thr 241Met (rs861539) with the susceptibility of lung cancer in Saudi population

This study demonstrated the association of polymorphisms in ERCC2 (Asp312Asn) rs1799793, ERCC2 (Lys751Gln) rs13181, XRCC1 (Arg399Gln) rs25487 and XRCC3(Thr241Met) rs861539 polymorphisms with a susceptibility of lung cancer (LC) onset in the Saudi population. The study was performed on 134 LC patients and 270 controls. The data revealed that there was no significant association of LC with subtype squamous cell carcinoma (SCC), small cell lung cancer (SCLC) and adenocarcinoma with the ERCC2 rs1799793 polymorphism. The data showed that the CC genotype for ERCC2 rs13181, the AA genotype for XRCC1 rs25487, and the genotype TT for XRCC3 rs861539 were significantly associated with SCC susceptibility (p < 0.05). Similarly, the CC genotype for ERCC2 rs13181 and the AA genotype for XRCC1 rs25487 were significantly associated with adenocarcinoma susceptibility (p < 0.05). Whereas, the TT genotype for XRCC3 rs861539 was significantly associated with SCLC susceptibility (p = 0.005). In total, significant association of LC susceptibility was found in the following combination models of recessive genotypes: AC heterozygous for ERCC2 rs13181 + AA homozygous for XRCC1 rs25487, CC homozygous for ERCC2 rs13181 + GA heterozygous for rs25487, CC homozygous for rs13181 + AA homozygous for XRCC1 rs25487, CC homozygous for ERCC2 rs13181 + TT homozygous for XRCC3 rs861539, GA heterozygous for XRCC1 rs25487 + CT heterozygous for XRCC3 rs861539, GA heterozygous for XRCC1 rs25487 + TT homozygous for XRCC3 rs861539, AA homozygous for XRCC1 rs25487 + CT heterozygous for XRCC3 rs861539, AA homozygous for XRCC1 rs25487+ TT homozygous for XRCC3 rs861539. These data clearly demonstrated that the combination of recessive genotypes may be associated with susceptibility of LC onset (p < 0.05). In short, the data indicated that DNA repair genes increase LC risk via gene-gene interaction rather than independent variants.

ERCC1 19007 Polymorphism in Greek Patients with Advanced Urothelial Cancer Treated with Platinum-Based Chemotherapy: Effect of the Changing Treatment Paradigm: A Cohort Study by the Hellenic GU Cancer Group.

We previously showed that ERCC1 19007 C>T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease.

Impact of ERCC2 Lys751Gln (rs13181), ERCC2 Asp312Asn (rs1799793) and XRCC1 Arg399Gln (rs25487) polymorphisms on the risk of prostate cancer among cases from the central region of Saudi Arabia

This study was undertaken to investigate an association between genetic variants of ERCC2 (Lys751Gln), ERCC2 (Asp312Asn) or XRCC1 (Arg399Gln) polymorphisms with the risk of prostate cancer (PC) in Saudi population. This is a case-control study conducted on 124 PC patients and 425 healthy human controls. Blood samples were used for DNA extraction and gene polymorphisms for ERCC2 (Lys751Gln), ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln). The risk of the associations was calculated by odds ratio (OR) and 95% confidence interval (CI). The data demonstrated no significant associations between ERCC2 (Lys751Gln) polymorphism and PC risk, whereas ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms were found to be significantly associated with PC risk (OR of 2.2, 95% CI, 1.1–4.1; p = 0.02) and (OR of 2.4, 95% CI, 1.3–4.5; p = 0.005), respectively. Likewise, recessive genotype models also showed significant association of ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms with PC risk (p = 0.009). Interestingly, these genetic associations were more pronounced in aged populations (p = 0.003) as well as in smokers (p < 0.0001). Combination of ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) genotypes showed strong association with the risk of PC onset (p < 0.001). These novel findings indicate that ERCC2 (Lys751Gln) polymorphism was not associated with risk of PC, whereas ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms showed strongly associated with the increased risk of PC. Combination of ERCC2 (Asp312Asn) and XRCC1 (Arg399 Gln) genotypes also showed strong association with increased risk of PC. In addition, more risk of PC onset was noticed in aged population and for those who were reported to have smoking history.

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.

Genetic polymorphisms of GSTP1, XRCC1, XPC and ERCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer patients of Bangladesh.

Inter-individual genetic makeup can trigger variability in platinum-based chemotherapeutic responses and corresponding adverse drug reactions and toxicities. Exploring the genetic causes behind these inter-individual variabilities in platinum-based chemotherapeutic responses by investigating the effects of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genetic polymorphisms on toxicity and therapeutic response of this treatment among Bangladeshi advanced non-small cell lung cancer (NSCLC) patients was the aim of this study. 285 Clinically proven either stage IIIB or IV (advanced) NSCLC patients aging not less than 18years old and receiving platinum-based chemotherapy were recruited to assess the influence of these four single nucleotide polymorphisms (SNPs) on peripheral leukocytes. Toxicity and response were evaluated by multivariate regression analyses using SPSS statistical software (version 17.0). XRCC1 (rs25487) polymorphism was found to act as a predictive factor for not only grade 3 and 4 anemia (p = 0.008), neutropenia (p = 0.010), thrombocytopenia (p = 0.025) and gastrointestinal toxicity (p = 0.002) but also for therapeutic response (p = 0.012) in platinum-based chemotherapy. Although GSTP1 (rs1695) polymorphism might serve as prognostic factor regarding grade 3 or 4 neutropenia, a significant (p = 0.044) improvement in response to platinum-based chemotherapy was observed. However, XPC (rs2228001) and ERCC1 (rs11615) polymorphisms could not establish any significant relation with toxicity or therapeutic response. XRCC1 (rs2228001) and GSTP1 (rs1695) polymorphisms might explain platinum-induced clinical outcomes in terms of both toxicity and therapeutic response variations among Bangladeshi advanced NSCLC patients.

ERCC1, XRCC1, and GSTP1 Polymorphisms and Treatment Outcomes of Advanced Epithelial Ovarian Cancer Patients Treated with Platinum-based Chemotherapy.

Objective:The first line regimen for treating epithelial ovarian cancer (EOC) is platinum-based chemotherapy. Various factors impact its effectiveness including polymorphisms of enzymes in platinum-related metabolism processes. Methods:We conducted the study to investigate the association between polymorphisms of ERCC1, XRCC1 and GSTP1, which responsible for platinum’s metabolisms in Thai epithelial ovarian cancer patients. Results:Fifty-two patients with advanced epithelial ovarian cancer were enrolled into this study. Genotyping analysis of ERCC1 (C->A, rs3212986), XRCC1 (A->G, rs25487) and GSTP (A->G, rs1695) were performed which variant allele frequencies were found at 35.6%, 28.9% and 10.6%, respectively. Patients with homozygous variant type (A/A) of ERCC1 C8092A had higher rate of platinum-resistance (75% vs 16.7%, p =0.046). In addition, the significant association of GSTP1 polymorphism and grade 2 anemia was found. Patients with A/G genotype of GSTP1 had higher rate of grade 2 anemia (81.8% vs 46.3%, p =0.036). Conclusions:Genetic polymorphisms of ERCC1, and GSTP1 might be useful biomarkers for prediction of clinical benefit and toxicities of platinum-based chemotherapy in Thai epithelial ovarian cancer patients.

DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India.

Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell's ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13-2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene-gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

Influence of ABCB-1, ERCC-1 and ERCC-2 gene polymorphisms on response to capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer (CRC) patients of South India.

High interindividual response variability was reported with capecitabine and oxaliplatin (CAPOX) regimen in colorectal cancer (CRC). The single nucleotide polymorphisms (SNPs) of the genes related to drug efflux transport (ABCB1) and DNA repair (ERCC) could result in altered tumour response. Hence, this study was designed to assess the influence of ABCB1, ERCC-1 and ERCC-2 gene polymorphisms on tumour response to CAPOX treatment in CRC patients of South Indian origin. A total of 145 newly diagnosed CRC patients were included in the final analysis. Response to CAPOX treatment in the adjuvant setting was assessed in terms of disease-free survival rate (DFSR) and overall survival rate (OSR) at 3years, whereas in the palliative setting, the response was assessed as progression-free survival rate (PFSR) and OSR at 3years. Five millilitres of the venous blood sample was collected from each patient for genomic DNA extraction by the manual phenol-chloroform method. Genotyping and allelic discrimination analysis were done using real-time PCR (RT-PCR). With ABCB1 gene polymorphism rs1045642 (A>G), patients with AG/GG genotype showed better DFSR [P value=.02, OR=2 (CI: 1.5-3)] and PFSR [P value=.02, OR=1.6 (CI: 1.1-2.5)] when compared to AA genotype in the adjuvant and palliative settings, respectively. Similarly with rs1128503 (A>G) polymorphism, patients with AG/GG genotype were found to have better DFSR [P value=.02, OR=1.9 (CI: 1.3-3)] and PFSR [P value=.01, OR=2 (CI: 1.1-3.7)] when compared to AA genotype. However, we did not find any association between CAPOX response and ABCB1 gene polymorphisms in a binary logistic regression when non-genetic predictors were considered for analysis. We did not find any association with ERCC1 (rs11615 A>G) and ERCC2 (rs13181 T>G) gene polymorphisms with respect to CAPOX response in either of the treatment settings. The response to CAPOX treatment was found to be influenced by the ABCB1 gene variants (rs1128503 and rs1045642), thereby strengthening their predictive role. No association was found between ERCC1 (rs11615 A>G), ERCC2 (rs13181 T>G) gene polymorphisms and tumour response to CAPOX treatment in CRC patients of South Indian origin.

Impact of ERCC1 gene polymorphisms on response to cisplatin based therapy in oral squamous cell carcinoma (OSCC) patients.

Cisplatin is one of the major drugs that used in the treatment of oral cancer.Excision repair cross-complementation group 1 (ERCC1) is a key DNA repair gene in the nucleotide excision repair pathway which is activated in the repair of intra- and interstrand DNA crosslink caused by platinum-based treatment. The aim of this study was to investigate the association between polymorphisms in ERCC1 (C118T & C8092A) genes and the response to cisplatin-based chemotherapy. ERCC1polymorphisms (C118T & C8092A) were studied using PCR-RFLP method from 150 OSCC patients as cases as well as 150 normal tissues from the same patients were collected as controls for this study. Results: Frequencies of ERCC1 C118C, C118T and T118T genotypes were 60%, 28% and 12% in OSCC patients and 78%, 19% and 3% in the controls, respectively. The C118T & T118T genotype had a 1.69 and 4.97 -folds increased risk for OSCC. Frequencies of ERCC1 C8092C, C8092A and A8092A were 78%, 18% and 4% in the OSCC patients and 89%, 10%, amd 1% in the controls, respectively. The C8092A genotype showed a 1.97-fold increased risk for OSCC. In conclusion, this study highlights the DNA repair gene polymorphisms that might play a role in mediating susceptibility to oral squamous cell carcinoma and cisplatin therapy. Our data suggest that the ERCC1 C118T, T118T and ERCC1 C8092A genotypes are genetic risk factors for Oral squamous cell carcinoma and ERCC1 118 C/T and C8092A polymorphisms have significant influence on clinical outcome.

Association of ERCC1 and ERCC2 Gene Polymorphisms with Pancreatic Cancer Risk: A Meta-Analysis.

In this meta-analysis, all relative literature was retrieved through the Embase and PubMed databases. Moreover, the Stata 12.0 software package was applied to calculate the pooled odds ratio (OR) of the 95% confidence interval (CI). A total of seven studies was identified to analyze the relation between ERCC1 and ERCC2 gene polymorphisms and pancreatic cancer risk. The results showed that ERCC2 rs13181 polymorphism was associated with pancreatic cancer (CC vs. AA: OR = 1.53, 95% CI = 1.24-1.90; AC vs. AA: OR = 1.06, 95% CI = 0.92-1.22; dominant model: OR = 1.16, 95% CI = 1.02-1.32; recessive model: OR = 1.39, 95% CI = 0.13-1.70). For ERCC1 rs3212986 polymorphism, a significant correlation with pancreatic cancer risk was found (TT vs. GG: OR = 2.33, 95% CI = 1.73-3.14; GT vs. GG: OR = 1.34, 95% CI = 1.11-1.63; dominant model: OR = 1.50, 95% CI = 1.25-1.80; recessive model: OR = 1.98, 95% CI = 1.50-2.62). A lack of association was found for ERCC1 rs11615 polymorphism (TT vs. CC: OR = 1.21, 95% CI = 0.93-1.56; CT vs. CC: OR = 1.02, 95% CI = 0.87-1.21; dominant model: OR = 1.43, 95% CI = 0.80-2.50; recessive model: OR = 0.99, 95% CI = 0.65-1.51).