ERCC1 Rs11615 Research Articles

A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy.

Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.

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.

ERCC2 rs13181 Polymorphism Association with Glioma Risk: an Update Meta-Analysis.

Glioma is the most common type of primary brain tumour which accounts for about 30% of all brain and central nervous system tumours, and approximately 70% of adult malignant brain tumours. Numerous studies have been performed to assess the relationship between ERCC2 rs13181 polymorphism and the risk of glioma development, yet these findings of these studies are often inconsistent and contradictory. Therefore, the aim of this study is to conduct a systematic review and meta-analysis to assess the role of ERCC2 rs13181 in glioma developing. In this work, we have conducted a systematic review and meta-analysis. In order to collect the results of relevant studies on the association of ERCC2 rs13181 gene polymorphism with glioma, we initially searched the Scopus, Embase, Web of Science (WoS), PubMed, and ScienceDirect databases, without a lower time limit, and until June 2020. In order to analyse the eligible studies, the random effects model was used and the heterogeneity of the studies was investigated with the I 2 index. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2). The total number of studies that focused on patients with glioma was 10. The odds ratio of GG vs TT genotype in patients with glioma based on meta-analysis was 1.08 (0.85-1.37: 95% confidence interval), which indicates the increasing effect of GG vs TT genotype by 0.08. The odds ratio of GG + TG vs TT genotype in patients with glioma was 1.22 (1.38-1.7: 95% confidence interval) based on meta-analysis, which indicates the increasing effect of GG + TG vs TT genotype as 0.22. The odds ratio of TG vs TT genotype in patients with glioma was 1.2 (0.38-1.4: 95% confidence interval), which shows the increasing effect of TG vs TT genotype by 0.2. The odds ratio of G vs T genotype in patients with glioma based on the meta-analysis was 1.15 (1.26-1.4: 95% confidence interval), which indicates the increasing effect of G vs T genotype by 0.15. The odds ratio of GG vs TG + TT genotype in patients with glioma based on meta-analysis was 1.22 (1.33-1.45: 95% confidence interval), which indicates the increasing effect of GG vs TG + TT genotype by 0.22. The results of this systematic review and meta-analysis show that ERCC2 rs13181 polymorphism and its genotypes are an important risk factor for genetic susceptibility to glioma tumour.

Association between rs735482 polymorphism and risk of cancer: A meta-analysis of 10 case-control studies.

Several studies have inspected the relationship between rs735482 polymorphism and the risk of some human cancers, but the findings remain controversial. We designed this meta-analysis to validate the association between rs735482 polymorphism and cancer risk. All articles were published before September 1, 2018 and searched in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang, and Chinese BioMedical databases, STATA 12.0 software was used for statistical analysis, which provides reasonable data and technical support for this article. A total of 10 studies were included in the meta-analysis, including 2652 cancer cases and 3536 rs735482 polymorphic controls. Data were directly extracted from these studies and odds ratios with 95% confidence intervals were computed to estimate the strength of the association. By pooling all eligible studies, the rs735482 polymorphism showed no significant association with susceptibility of several cancers in all the five genetic models (the allelic model: OR = 1.019, 95% CI: 0.916–1.134, P = .731). In addition, another adjusted OR data showed a significant increased risk between the rs735482 and susceptibility of several cancers (the codominant model BB vs AA: OR = 1.353, 95% CI: 1.033–1.774, P = .028) and the stratification analysis by ethnicity indicated the rs735482 is associated with an increased risk of cancer in Chinese group (BB vs AA, OR = 1.391, 95% CI = 1.054–1.837, P = .020; AB+BB vs AA OR = 1.253, 95% CI = 1.011–1.551, P = .039). However, the ERCC1 rs735482 is associated with a decreased risk of cancer in Italian group (AB vs AA, OR = 0.600, 95% CI = 0.402–0.859, P = .012; AB + BB vs AA, OR = 0.620, 95% CI = 0.424–0.908, P = .014). The results of this meta-analysis do not support the association between rs735482 polymorphism and cancer risk. But stratified analysis showed that rs735482 significantly increased the risk of cancer in Chinese while decreased the risk of cancer in Italian. Because of the limited number of samples, larger and well-designed researches are needed to estimate this association in detail.

Genetic polymorphisms in DNA repair genes and their association with risk of cervical cancer: A systematic review and meta-analysis.

There have been a large number of epidemiologic studies regarding the association between genetic polymorphisms in DNA repair genes and onset of cervical cancer. However, results are inconsistent. Articles published before June 2021 and regarding genetic polymorphisms in DNA repair genes and cervical cancer were searched in following databases: PubMed, Web of Science, Google Scholar, and CNKI. With at least three articles for each polymorphism, we made meta-analysis to compute multivariate odds ratios (ORs) and their 95% confidence intervals (CIs). The present study showed significant associations between XRCC1 Arg399Gln polymorphisms and risk of cervical cancer in Asian, whereas no significant association between them were showed in Caucasian (Asian: GA vs. GG: OR = 1.27, 95%CI 1.06-1.52; AA vs. GG: OR = 1.91, 95%CI 1.29-2.83; GA + AA vs. GG: OR = 1.36, 95%CI 1.12-1.65; AA vs. GG + GA: OR = 1.66, 95%CI 1.17-2.37; Caucasian: GA vs. GG: OR = 1.08, 95%CI 0.83-1.41; AA vs. GG: OR = 2.18, 95%CI 0.75-6.31; GA + AA vs. GG: OR = 1.23, 95%CI 0.85-1.78; AA vs. GG + GA: OR = 1.70, 95%CI 0.69-4.18). In addition, there were significant associations between ERCC2 rs13181 polymorphisms and risk of cervical cancer in Asian (AC vs AA: OR = 0.53, 95%CI 0.37-0.75, I2 = 0.0%, p value of Q test = 0.847; AC + CC vs AA: OR = 0.50, 95%CI 0.36-0.70, I2 = 0.0%, p value of Q test = 0.856). The meta-analysis showed that there were significant associations between XRCC1 Arg399Gln and ERCC2 rs13181 polymorphisms and risk of cervical cancer.

Genetic Variations in Nucleotide Excision Repair Pathway Genes and Risk of Allergic Rhinitis

Background Allergic rhinitis (AR) is the most frequent inflammatory disorder in the nasal mucosa that remains unclear etiology. Mounting studies suggested that genetic instability could trigger and worsen the inflammatory response. The nucleotide excision repair (NER) system is an important pathway in maintaining the stability of the genome. Therefore, the genetic variations in NER pathway genes may have potential effects on AR risk. Methods We evaluated the correlation between 19 candidate single nucleotide polymorphisms (SNPs) in NER pathway genes and AR susceptibility by a case-control study in a Chinese population, which contains 508 AR cases and 526 controls. Results Three independent SNPs were identified as significantly associated with AR susceptibility, including ERCC1 rs2298881 C > A (recessive model: adjusted odds ratios (OR) = 0.30, 95%confidence interval (CI) = 0.18–0.50, P < 0.0001), ERCC1 rs11615 G > A (dominant model: adjusted OR = 1.44, 95%CI = 1.04–2.01, P = 0.030), and XPC rs2228001 A > C (dominant model: adjusted OR = 0.68, 95%CI = 0.49–0.95, P = 0.024). Stratified analysis showed that ERCC1 rs2298881 AA genotype was correlated with a lower risk of AR among all the subgroups compared with rs2298881 CC/CA genotype. XPC rs2228001 AC/CC genotype reduced AR risk among the following subgroups: age > 60 months, clinical stage I and III. Conclusion Our finding showed that genetic variations in NER pathway genes: ERCC1 and XPC may affect the risk of AR, which will provide new insights into the genetics of AR from the perspective of DNA damage repair.

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.

The Association of ERCC1 and ERCC5 Polymorphisms with Lung Cancer Risk in Han Chinese.

Background: Polymorphisms in DNA damage repair genes are important determinants for cancer susceptibility, clinical phenotype diversity, and therapy. However, their relationship with lung cancer remains unclear. This study aimed to investigate the role of DNA damage repair gene polymorphisms in the risk of lung cancer.Methods: The matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy-based genotyping system was used to genotype 601 individuals (200 lung cancer patients and 401 age- and sex-matched healthy controls) for polymorphisms in excision repair cross-complementing group 1 (ERCC1) and ERCC5 genes.Results: The ERCC5 rs4771436 GG genotype, recessive model (GG vs. GT+TT), and the ERCC5 rs1047768 recessive model (CC vs. CT+TT) were associated with significantly increased risks of lung cancer (P=0.029, P=0.014, and P=0.044, respectively), especially in men and individuals aged 60 years or younger.Conclusion: ERCC5 rs4771436 and rs1047768 genotypes were associated with an increased risk of lung cancer, suggesting that polymorphisms in DNA repair genes are significantly related to the risk of lung cancer, and play an important role in the occurrence of lung cancer.

The link of ERCC2 rs13181 and ERCC4 rs2276466 polymorphisms with breast cancer in the Bangladeshi population.

Breast cancer (BC) is the most common disease in women and the leading cause of death from cancer globally. Epidemiological studies examined that nucleotide excision repair genes ERCC2 (rs13181) and ERCC4 (rs2276466) SNPs might increase cancer risk. Based on the previous investigation, this study was conducted to explore the correlation between these polymorphisms and BC susceptibility in Bangladeshi women. Between January 2019 and January 2020, 140 blood samples were collected from female patients histologically diagnosed with BC, and 111 female controls were recruited from non-cancer subjects. Genotyping was performed applying the PCR-RFLP method, and all statistical analyzes were conducted using SPSS, version 25.0. Comparison of characteristics and clinicopathological features between ERCC2 rs13181 and ERCC4 rs2276466 carriers and non-carriers showed no significant link with BC. Analysis of ERCC2 rs13181 with the risk of BC showed that the GG genotype and G allele carriers showed a fourfold and 1.78-fold higher risk (OR 4.00, P = 0.001 and OR 1.78, P = 0.002) that are statistically significant. In addition, the patients with combined TG+GG genotype revealed a 2.09-fold increased chance (OR 2.09, P = 0.020) BC development. Analysis of recessive model (GG vs. TT+TG) also depicted 2.74-times significantly higher risk (OR 2.74, P = 0.002). On the other hand, ERCC4 rs2276466 polymorphism did not show any significant association with BC (P > 0.05). Our findings show that ERCC2 rs13181 is linked to an elevated risk of BC. Our study also shows that ERCC4 rs2276466 polymorphism has no substantial risk of BC in the Bangladeshi population.

Pharmacogenetic markers of chemotherapy toxicity in gastrointestinal tumors: a preliminary analysis

Aim. To assess the association between the carriage of minor allelic variants of 8 genes that encode key enzymes involved in the metabolism of anticancer drugs (DPYD, GSTP1, MTHFR, UGT1A1) and cell repair (XPC, ERCC1, TYMP, NQO1) and the severity of adverse drug events in patients with common gastrointestinal tumors. Tasks. To study the frequency of minor allelic variants of the DPYD, GSTP1, MTHFR, UGT1A1, XPC, ERCC1, TYMP, NQO1 genes; to assess the frequency and severity of adverse drug events of chemotherapy treatment in the study population. Materials and methods. For the period from October 2020 to April 2021, 56 patients (women 29, men 27) with verified malignant tumors of the gastrointestinal tract were included in a prospective clinical study as a part of the RSF grant No. 20-75-10158. The mean age was 62.311.4 years. Colon cancer was detected in 24 patients, tumors of the esophagus and stomach in 19 patients, tumors of pancreas and biliary tract in 13 patients. First-line palliative chemotherapy was given to 27 patients, adjuvant 19 patients, neoadjuvant 10 patients. All patients had not previously received cytotoxic or radiation treatment. Point nucleotide variants of genes DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, TYMPS, NQO1 were determined by hybridization analysis on biological microchips. Differences in the tolerance of cytotoxic therapy (5-fluorouracil, platinum preparations, irinotecan) depending on the genotype were assessed using Fishers exact test. Results. The average number of chemotherapy courses received was 4.22.6 (112). There was a statistically significant difference in the tolerability of chemotherapy in patients with minor allelic variants of the GSTP1 rs1695 (p=0.03), ERCC1 rs11615 (p=0.01), and UGT1A1 rs8175347 (p=0.003) genes. Conclusion. The use of hybridization analysis on biological microchips to assess allelic variants responsible for the tolerability of cytotoxic therapy is reasonable and requires further prospective assessment.

Genetic polymorphisms and haplotypes of ERCC1 and ERCC2 associated with quality of life, depression, and anxiety status among patients with lung cancer

BackgroundPatients with lung cancer (LC) have a poor quality of life (QoL) and easily suffer from psychological diseases. Previous studies focused less on the relationship between genetic factors and QoL, depression, and anxiety status in LC patients. The current study is intended to explore the relationship between SNPs and haplotypes of ERCC1 and ERCC2 and the QoL, depression and anxiety status of patients with LC.MethodsQoL, depression and anxiety status were assessed in 291 LC patients using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), SDS and SAS. Nine tag SNPs of ERCC1 and ERCC2 were detected using an improved multiplex ligation detection reaction (iMLDR) technique. Haplotype analysis was conducted using the software Haploview 4.2. The association between SNPs or haplotypes and QoL or depression or anxiety in LC patients was analyzed by regression analysis.ResultsERCC1 rs11615 was associated with emotional functioning (P = 0.027), and ERCC1 rs3212986 was associated with anxiety scores (P = 0.018). ERCC1 rs762562-rs3212986 haplotype was associated with cognitive function (P = 0.029), somatic function (P = 0.014) and dysphagia (OR = 3.32, P = 0.044). Patients with ERCC1 rs3212986-rs11615 AG haplotype had worse cognitive function (adjusted Beta = − 5.42) and somatic function (adjusted Beta = − 6.55) and had severer symptoms of loss of appetite (adjusted OR = 1.67) and dysphagia (adjusted OR = 4.43) (All adjusted P < 0.05). ERCC2 rs13181-rs3916874-rs238416 haplotype was associated with emotional functioning (P = 0.035), pain at other sites (OR 1.88, P = 0.014), chest pain (OR 0.42, P = 0.02), dysphagia (OR 2.82, P = 0.048), and anxiety status (OR 0.23, P = 0.009).ConclusionAfter adjustment for environmental factors, SNPs and haplotypes of ERCC1 and ERCC2 were associated with different domains of QoL, depression and anxiety in LC patients.

Bisphenol A exposure, interaction with genetic variants and colorectal cancer via mediating oxidative stress biomarkers

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF2α (8-isoPGF2α), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF2α were significantly positively associated with BPA (P < 0.05). The mediation analysis showed BPA-associated HNE-MA significantly mediated 11.81% of the effect of BPA on CRC risk. Moreover, BPA was found to interact with ERCC5 rs17655 and rs2296147 (both Pmultiplicative < 0.05) to increase CRC risk. In brief, our results suggested BPA was associated with CRC risk and the positive association of BPA with CRC risk might be partly mediated by the oxidative stress HNE-MA. BPA might interact with ERCC5 rs17655 and rs2296147 to increase CRC risk.

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.

BackgroundThe most frequently reported treatment‐related adverse event in clinical trials with the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.Materials and Methods ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib‐treated patients from PALOMA‐2 (n = 584) and PALOMA‐3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non‐Asian (n = 530) ethnicity. Median progression‐free survival (mPFS) was estimated using the Kaplan‐Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed.Results ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non‐Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615−13.922, p < .0001; Non‐Asians: OR, 6.884, 95% CI, 4.138−11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311−1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901−3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non‐Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype.ConclusionThis is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135).Implications for PracticePalbociclib plus endocrine therapy improves hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy‐induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non‐Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.

The association between the ERCC1/2 polymorphisms and radiotherapy efficacy in 87 patients with non-small cell lung cancer.

BackgroundThis study sought to investigate the association between the ERCC1/2 single-nucleotide polymorphisms (SNPs) and the efficacy of radiotherapy and prognosis in patients with non-small cell lung cancer (NSCLC).MethodsWe examined 6 SNPs in the ERCC1 and ERCC2 genes in 87 consecutive patients with NSCLC who were treated with definitive radiotherapy. The objective remission rates (ORR), overall survival (OS), and progressive-free survival (PFS) were assessed. A Cox regression analysis was conducted to analyze the independent factors related to death and recurrence.ResultPatients with the G allele had better OS than patients with the A allele, and there was a statistical difference between the two groups (30.9 vs. 16.2 months; P=0.003). Patients with the AA genotype had significantly worse OS than patients with the AG or GG genotypes (6.8 vs. 19.8 vs. 30.9 months, respectively; P=0.000). The median PFS of the G allele was 18.9 months, which was significantly better than that of the A allele (P=0.040). The median PFS of patients with the GG genotype, the AG genotype, and the AA genotype was 18.9, 11.3, and 5.1 months, respectively; the difference among the three groups was statistically significant (P=0.019). Patients with the G allele also had better PFS than those with the A allele (18.9 vs. 11.3 months, P=0.040). The multivariate cox proportional hazard analysis showed that the ERCC1 gene rs11615 was an independent survival indicator [HR: 1.623, 95% confidence interval (CI): 1.018–2.591, P=0.042] but not an independent recurrence indicator (HR: 1.497, 95% CI: 0.932–2.404, P=0.095).ConclusionsThe ERCC1 rs11615 SNP may be a potential biomarker for predicting survival prognosis in Chinese NSCLC patients who have undergone definitive radiotherapy. Patients with the G allele had better OS than those with the A allele.

Effect of TOP2A and ERCC1 gene polymorphisms on the efficacy and toxicity of cisplatin and etoposide-based chemotherapy in small cell lung cancer patients.

IntroductionThe main treatment regimen for small cell lung cancer (SCLC) involves platinum-based chemotherapy (cisplatin or carboplatin) and etoposide. Single nucleotide polymorphisms (SNPs) in TOP2A and ERCC1 genes were tested as prognostic and predictive factors in non-small cell lung cancer (NSCLC). There are limited data about the clinical relevance of these genetic alterations in SCLC. We undertook this retrospective study to determine the influence of SNPs in TOP2A (rs34300454; rs13695; rs11540720) and ERCC1 (rs11615; rs3212986) genes on the efficiency and toxicity of chemotherapy with platinum and etoposide in SCLC Caucasian patients.Material and methodsThe studied group included 103 Caucasian SCLC patients (65 male, 38 female, median age 65 ±7.5 years). Detailed clinical-demographical data were collected and response to treatment was monitored. DNA was isolated from peripheral blood leukocytes using QIAamp DNA Mini Kit. Single nucleotide polymorphisms were analyzed using TaqMan hydrolyzing probes in real-time PCR technique on an Eco Illumina device.ResultsPatients with C/C genotype in rs13695 of the TOP2A gene had significantly lower risk of neutropenia during chemotherapy than C/T heterozygous patients (p = 0.02, χ² = 5.51, OR = 2.676, 95% CI: 1.165–6.143). Patients harbouring homozygous C/C genotype in rs3212986 of the ERCC1 gene had significantly higher risk of anaemia during chemotherapy, than heterozygous C/A patients (p = 0.045, χ² = 4.01, OR = 0.417, 95% CI: 0.175–0.991). Furthermore, heterozygous G/A genotype in rs11615 of the ERCC1 gene was associated with significant shortening of OS (9 vs. 12 months) compared to homozygous A/A genotype (p = 0.01, χ² = 6.31, HR = 1.657, 95% CI: 1.0710–2.5633).ConclusionsSNPs in ERCC1 and TOP2 genes may be associated with the toxicities and survival of SCLC patients treated with cisplatin and etoposide.

Association Studies of ERCC2 rs13181 Polymorphism with Pancreatic Cancer Susceptibility.

Although the ERCC2 gene rs13181 polymorphism is involved in the pancreatic cancer pathogenic mechanism, there is no consistent finding. This meta-analysis aimed to determine the association between ERCC2 rs13181 polymorphism and pancreatic cancer. Related articles were searched against the PubMed database in a retrospective way. Additionally, the combined odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated using the random- or fixed-effects model. Altogether, seven articles regarding ERCC2 gene rs13181 polymorphism were enrolled. The combined ORs regarding the relationship of ERCC2 rs13181 polymorphism with pancreatic cancer incidence showed significant differences in each genetic model (C vs. A: OR = 1.14, 95% CI = 1.04-1.26; CC vs. AA: OR = 1.53, 95% CI = 1.24-1.90; AC vs. AA: OR = 1.06, 95% CI 0.92-1.22; recessive model: OR = 1.50, 95% CI = 1.22-1.84; dominant model: OR = 1.16, 95% CI = 1.02-1.32). Additionally, we performed subgroup analysis stratified by race, which revealed that ERCC2 rs13181 polymorphism increased the risk of pancreatic cancer in Asian populations. This work suggests that the ERCC2 gene rs13181 polymorphism is related to pancreatic cancer risk in Asians.

Association of ERCC gene polymorphism with osteosarcoma risk

The relationship between ERCC gene polymorphism and osteosarcoma risk / overall survival of osteosarcoma is still conflicting, and this meta-analysis was performed to assess these associations. The association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method. Four studies were included for the association of ERCC gene polymorphism with osteosarcoma risk, and nine studies were recruited into this meta-analysis for the relationship between ERCC gene polymorphism and overall survival of osteosarcoma. The meta-analysis indicated that ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (A>G) gene polymorphism, ERCC2 rs13181 (Lys751Gln) gene polymorphism were not associated with osteosarcoma risk. ERCC1 rs2298881 (C>A) gene polymorphism, ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (Asp312Asn) gene polymorphism were not associated with overall survival of osteosarcoma. Interestingly, ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma, but AA genotype not (A allele: OR = 0.78, 95% CI: 0.65-0.93, P = 0.007; GG genotype: OR = 1.32, 95% CI: 1.05-1.65, P = 0.02; AA genotype: OR = 0.69, 95% CI: 0.45-1.04, P = 0.08). ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma.

Polymorphisms in the BER and NER pathways and their influence on survival and toxicity in never-smokers with lung cancer

Polymorphisms in DNA repair pathways may play a relevant role in lung cancer survival in never-smokers. Furthermore, they could be implicated in the response to chemotherapy and toxicity of platinum agents. The aim of this study was to evaluate the influence of various genetic polymorphisms in the BER and NER DNA repair pathways on survival and toxicity in never-smoker LC patients. The study included never-smokers LC cases diagnosed from 2011 through 2019, belonging to the Lung Cancer Research In Never Smokers study. A total of 356 never-smokers cases participated (79% women; 83% adenocarcinoma and 65% stage IV). Survival at 3 and 5 years from diagnosis was not associated with genetic polymorphisms, except in the subgroup of patients who received radiotherapy or chemo-radiotherapy, and presented with ERCC1 rs3212986 polymorphism. There was greater toxicity in those presenting OGG1 rs1052133 (CG) and ERCC1 rs11615 polymorphisms among patients treated with radiotherapy or chemo-radiotherapy, respectively. In general, polymorphisms in the BER and NER pathways do not seem to play a relevant role in survival and response to treatment among never-smoker LC patients.

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity.A retrospective cohort study was conducted in 194 CRC patients.In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009).ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.