DNA repair gene polymorphism associated with sensitivity of lung cancer to therapy

This study aimed to investigate association between single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing gene 1 (ERCC1), excision repair cross-complementing gene 2 (ERCC2), and X-ray repair cross-complementing group 1 (XRCC1) with sensitivity of advanced non-small cell lung cancer (NSCLC) patients to platinum-based chemotherapy. A total of 89 NSCLC patients were recruited and treated with two cycles of platinum-based chemotherapy. DNA was extracted from peripheral lymphocytes for detection of SNPs of ERCC1 Asn118Asn, ERCC2 Lys751Gln, and XRCC1 Arg399Gln. The overall response rate of these patients was 29.2%. There was no statistically significant difference of treatment response between the wild genotypes and the variant genotypes for the ERCC1 Asn118Asn and ERCC2 Lys751Gln gene. The distributions of genotypes XRCC1 Arg399Gln differed significantly between the response and non-response groups (76.9 vs. 23.1%, P = 0.001). The XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95%CI = 1.778-13.013, P = 0.002). The combination of the favorable genotypes of ERCC1, ERCC2, and XRCC1 had a higher response rate compared to that of patients with other genotypes. The combined polymorphisms of ERCC1, ERCC2, and XRCC1 may be associated with sensitivity of NSCLC to platinum-based chemotherapy. Further studies will verify these SNPs as biomarkers for prediction of platinum-based chemotherapy responses of NSCLC patients.     

Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy

To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments.     

Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.

DNA repair is a critical mechanism of resistance to platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Increased ERCC1 mRNA levels are related directly to platinum resistance in various cancers. We examined the association between two polymorphisms of ERCC1, codon 118 C/T and C8092A, which are associated with altered ERCC1 mRNA levels and mRNA stability, and overall survival (OS) in 128 advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. The two polymorphisms were in linkage disequilibrium. There was a statistically significant association between the C8092A polymorphism and OS (P = 0.006, by log-rank test), with median survival times of 22.3 (C/C) and 13.4 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with poor outcome. No statistically significant association was found for the codon 118 polymorphism and OS (P = 0.41, by log-rank test), with median survival times of 19.9 (T/T), 16.1 (C/T), and 13.3 (C/C) months, respectively. In conclusion, the ERCC1 C8092A polymorphism may be a useful predictor of OS in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.     

Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.

PURPOSE: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen. EXPERIMENTAL DESIGN: Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-na?ve, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp(312)Asn and Lys(751)Gln, ERCC1 C118T, and CDA Lys(27)Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's chi(2) tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. RESULTS: The CDA Lys(27)Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade > or =3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys(27)Lys polymorphism. CONCLUSIONS: Our data suggested the role of CDA Lys(27)Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys(27)Lys CDA and offer a potential new tool for treatment optimization.     

Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy

ERCC1 (excision repair cross-complementation group 1) and XPD (ERCC2, excision repair cross-complementation group 2) as genes have been known to be belonged to the nucleotide excision repair pathway and therefore related to DNA repair. Polymorphisms in these genes have been rarely evaluated in terms of predicting cancer patient survival. We investigated whether these polymorphisms have an effect on response to chemotherapy and survival in 109 patients with non-small-cell lung cancer treated with cisplatin combination chemotherapy. Polymorphisms of ERCC1 Asn118Asn (C --> T), XPD Lys751Gln (A --> C) and Asp312Asn (G --> A) were evaluated using a SNaPshot kit. As for chemotherapy response, treatment response did not show statistically significant differences between the wild genotypes and the variant genotypes for the ERCC1 and XPD gene. The median survival time of all patients was 376 days (95% CI, 291-488). As for survival rate according to the polymorphism of codon 118 in ERCC1, median survival time in patients showing C/C genotype was 486 days (95% CI, 333-x), which was significantly different from the 281 days (95% CI, 214-376) of patients with the variant genotype (T/T or C/T) (P = 0.0058). Using the Cox-proportional hazards model, the polymorphism of codon 118 in ERCC1, response to chemotherapy, weight loss and performance status effected overall survival significantly (P = 0.0001, 0.0001, 0.0028 and 0.0184, respectively). However, polymorphisms of codons 751 and 312 in the XPD gene did not affect patient survival (P = 0.4711 and 0.4542, respectively). Therefore, we suggest that the C/C genotype in codon 118 of ERCC1 is a surrogate marker for predicting better survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.     

非小细胞肺癌疗效预测因子基因多态性的研究

     切除交错互补修复基因、核糖核苷酸还原酶M1亚单位、P53、表皮生长因子受体、血管表皮生长因子与非小细胞肺癌（NSCLC）的疗效及预后密切相关。近年来,许多研究对上述因子的多态性与NSCLC疗效及预后进行相关探讨,其基因多态性有望成为NSCLC患者的预后预测标志。     

核苷酸切除修复交叉互补基因1 mRNA表达与非小细胞肺癌铂类化疗患者预后的相关性

目的 探讨核苷酸切除修复交叉互补基因1(ERCC1)mRNA表达与非小细胞肺癌(NSCLC)铂类化疗患者临床病理特征的关系及其预后意义.方法 采用实时荧光定量逆转录聚合酶链反应(RT-PCR)方法,检测NSCLC石蜡包埋组织中ERCC1 mRNA的表达水平,并比较其表达水平与NSCLC铂类化疗患者临床病理特征和生存时间之间的关系.结果 61例NSCLC患者中,ERCC1 mRNA的中位表达量为0.48.ERCC1 mRNA表达与NSCLC患者临床病理特征无关.ERCC1mRNA低表达(<0.35)患者经铂类药物化疗后的无进展生存时间为14.3个月,而高表达者为8.0个月,差异有统计学意义(P=0.028).ERCC1 mRNA低表达(<0.28)患者的总生存时间为28.4个月,而高表达者为12.9个月,差异有统计学意义(P=0.0064).Cox多因素回归分析显示,ERCC1 mRNA表达水平是影响NSCLC患者预后的独立因素.结论 ERCC1 mRNA的表达水平可以作为以铂类为基础药物化疗的NSCLC患者预后的独立预测因素,ERCC1 mRNA低表达的NSCLC患者经铂类化疗后,总生存时间明显延长,为制定NSCLC个体化的化疗方案提供了重要信息.     

Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer.

BACKGROUND: The aim of this study was to determine whether expressions of the excision repair cross-complementing (ERCC1), thymidylate synthase (TS), and glutathione S-transferase P1 (GSTP1) predict clinical outcome in patients with advanced gastric cancer treated with fluorouracil (5-fluorouracil)/oxaliplatin chemotherapy. PATIENTS AND METHODS: The study population consisted of 64 advanced gastric cancer patients (median age 51 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion at day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by 5-FU bolus 400 mg/m(2) and 22-h continuous infusion of 600 mg/m(2) at days 1-2. Treatment was repeated in 2-week intervals. The expressions of ERCC1, TS, and GSTP1 of primary tumors were examined by immunohistochemistry. RESULTS: The positive rates of ERCC1, TS, and GSTP1 were 70.3%, 29.7%, and 50.0%, respectively. The patients without ERCC1 expression were more likely to respond to chemotherapy (P = 0.045). There were no significant differences between response and TS or GSTP1 expression pattern (P = 0.813, P = 0.305, respectively). Median overall survival (OS) was significantly longer in patients without ERCC1 expression (P = 0.0396). TS or GSTP1 expression were not related to survival (P = 0.4578, P = 0.8121, respectively). Multivariate analysis revealed that ERCC1 expression significantly impacted on OS (hazard ratio 1.92, P = 0.037). CONCLUSION: Immunohistochemical studies for ERCC1 may be useful in prediction of the clinical outcome in advanced gastric cancer patients treated with 5-FU and oxaliplatin.     

ERCC1 mRNA表达与结直肠癌标准方案化疗临床预后的相关性研究

目的:探讨结直肠癌石蜡组织中切除修复交叉互补基因 (excision repair cross-complementing group 1,ERCC1) mRNA表达水平与接受标准方案化疗的结直肠癌患者临床病理的关系以及其预后意义。方法:采用实时荧光定量 RT-PCR检测福尔马林固定－石蜡包埋的结直肠癌组织中DNA修复基因ERCC1 mRNA的表达水平,并比较其表达水平与接受标准方案化疗的结直肠癌患者的临床病理及生存期之间的关系。结果:ERCC1 mRNA表达与结直肠癌临床病理特征无相关性(P＞0.05)。将ERCC1 mRNA在96例大肠癌患者中的表达量（相对于β-actin）分为低表达组与中高表达组（≤5.21为低表达组,＞5.21为中高表达组）,样本总生存期呈正态分布,中高表达组平均总生存期为68.52月（95%CI:63.06-76.06）,低表达组平均总生存期为56.63月（95%CI:44.45-68.80）,从生存曲线上看中高表达组患者总生存时间明显长于低表达组,两者有统计学差异(P=0.049)。样本无进展生存期呈偏态分布,中高表达组的中位生存时间30.98月（95%CI:0-18.65）,低表达组的中位生存时间8.48月（95%CI:6.37-10.60）,两者之间差别无统计学意义（P=0.575）。Cox多因素回归分析发现性别（P=0.023）、分期（P＜0.001）、以肠梗阻或肠穿孔起病（P=0.046）是患者总生存期的独立影响因素,年龄（P=0.043）、分期（P＜0.001）、脉管侵犯（P=0.002）是患者无进展生存期的独立影响因素。结论:ERCC1 mRNA的表达水平可能是使用标准方案化疗的结直肠癌患者预后的影响因素,性别、分期、以肠梗阻或肠穿孔起病、年龄、脉管侵犯是影响结直肠患者预后的独立影响因素。     

Multicenter phase II study of gemcitabine and oxaliplatin in advanced nasopharyngeal carcinoma—correlation with excision repair cross-complementing-1 polymorphisms

Background:Nasopharyngeal carcinoma (NPC) is a platinum-sensitive cancer and excision repair cross-complementing group 1 (ERCC1) polymorphisms have been shown to predict survival in several cancers following platinum therapy.Patients and methods:This multicenter study evaluated the activity of oxaliplatin and prolonged infusion of gemcitabine (‘GEMOX’ regimen) in recurrent NPC. Baseline blood samples were genotyped for the presence of ERCC1-118 gene polymorphisms.ResultsForty-two patients were recruited, of whom most (61%) had metastatic disease. Of the 40 patients evaluated for response, the respective overall response and disease control rates were 56.1% and 90.2%. At a median follow-up of 14.8 months, the respective median overall survival and time to progression were 19.6 months [95% confidence interval (CI) = 12.8–22 months] and 9 months (95% CI = 7.3–10 months). Grade 3–4 toxic effects were uncommon. The distribution of ERCC1-118 genotypes from 29 patients was C/C (n = 17, 40.5%), C/T (n = 10, 23.8%) and T/T (n = 2, 4.8%). No differences in survival or response rates were found between genotypes.Conclusions:GEMOX is active in the treatment of recurrent NPC. Detection of single-nucleotide gene polymorphisms from genomic DNA in peripheral blood is feasible in NPC and further studies are warranted.     

ERCC1和XRCC1多态性与进展期非小细胞肺癌对铂类化疗的敏感性

目的探讨DNA修复基因ERCC1 118C/T和XRCC1 Arg194Trp多态性与进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者铂类药物化疗敏感性的关系。方法采用PCR-RFLP技术检测149例经病理确诊的接受含铂两药方案化疗的NSCLC患者外周血ERCC1 118和XRCC1 194位点的基因型,并分析其与化疗疗效的关系。结果经2个周期化疗后,149例进展期NSCLC患者化疗有效率为32.9%。携带至少1个ERCC1 118T突变基因患者的化疗有效率至少是C/C野生型基因携带者的3倍(49.1%vs 23.4%,OR=3.156,95%CI:1.548～6.334,P=0.001)。携带至少1个XRCC1 194Trp突变基因患者的化疗有效率显著高于Arg/Arg基因型携带者(41.3%vs 23.2%,OR=2.326,95%CI:1.138～4.753,P=0.019)。ERCC1 118C/T和XRCC1 Arg194Trp 2个基因多态之间存在一定的联合作用,携带至少1个ERCC1 118 T突变基因同时又携带至少1个XRCC1 194Trp突变基因型者的化疗有效率明显高于同时携带ERCC1 118C/C和XRCC1 194Arg/Arg野生型基因者(66.7%vs 17.1%,OR=9.714,95%CI:3.104～30.406,P<0.001)。结论与单基因检测比较,2个基因的联合检测在预测铂类药物化疗敏感性中的价值更大。ERCC1 118和XRCC1 194基因多态联合与NSCLC患者对铂类药物化疗敏感性相关,ERCC1和XRCC1基因型的联合检测有可能成为预测铂类药物化疗敏感性的指标。     

ERCC polymorphisms and prognosis of patients with osteosarcoma

Osteosarcoma is the most common primary bone malignancy in children and teenagers, and its clinical outcome remains poor. Previous studies have investigated the association between excision repair cross-complementing (ERCC) and prognosis of osteosarcoma patients, but their results were inconsistent. We aimed to clarify the associations between ERCC polymorphisms and osteosarcoma prognosis by using meta-analysis. We searched relevant studies in PubMed, Embase, coupled with Chinese National Knowledge Infrastructure (CNKI) in human osteosarcoma published prior to April, 2014. Hazard ratios (HR) together with their 95 % confidence intervals (95 % CI) were used to measure the relationship between ERCC mutations and prognosis in patients with osteosarcoma. Pooled results showed that polymorphism of ERCC2 Lys751Gln was associated with the overall survival of osteosarcoma (GG vs. AA, HR?=?0.40; 95 % CI 0.18–0.86), and ERCC5 His46His mutation was associated with the event-free survival of osteosarcoma (CC vs. TT, HR?=?0.37; 95 % CI 0.15, 0.93). In addition, there is no evidence of association on ERCC1 Asn118Asn, ERCC1 Gln504Lys, and ERCC2 Asp312Asn polymorphisms with prognosis in osteosarcoma. In summary, the ERCC2 Lys751Gln and ERCC5 His46His polymorphisms might influence osteosarcoma prognosis.     

ERCC1和XRCC3基因多态性在接受含铂方案化疗NSCLC中的疗效预测作用

[目的]探讨DNA修复基因ERCC1 118和XRCC3 241多态性对于接受一线含铂化疗方案的非小细胞肺癌（NSCLC）患者的疗效预测作用。[方法]130例晚期接受含铂化疗的NSCLC患者进入研究．应用Taqman探针结合实时荧光PCR方法分析其外周血基因多态性．分析ERCC1 118和XRCC3 241多态性与疗效、疾病进展时间和总体生存期之间的关系。[结果]130例患者的总体有效率为20％．中位生存时间为15个月．ERCC1 118和XRCC3 241多态性与疗效无显著相关性。ERCC1 118基因型C/T或T/T患者的生存时间显著延长（P=0.003）。Cox多因素分析显示,ERCC1 118基因型C/T或T/T以及化疗有效患者的生存期显著延长。[结论]DNA修复基因ERCC1 118基因型C／T或T/T多态性可以延长NSCLC患者铂类治疗后的生存时间．     

EGF61A>G polymorphism as predictive marker of clinical outcome to first-line capecitabine and oxaliplatin in metastatic colorectal cancer

BackgroundThe purpose of the present study was to investigate polymorphisms related to the metabolism of fluoropyrimidine and oxaliplatin, thymidylate synthase (TS) and excision repair cross-complementing gene 1 (ERCC1) 118, in metastatic colorectal cancer patients treated with capecitabine and oxaliplatin (XELOX). We also investigated the importance of the EGF61A>G polymorphism, which holds a functional influence on the tyrosine kinase receptor regulation.Materials and methodsWe included 68 patients treated with first-line XELOX. Polymorphism analyses were carried out on pretreatment blood samples. Response was evaluated according to the RECIST. Survival analysis was described by the Kaplan–Meier method and log-rank testing.ResultsThe overall response rate was 38% and the median overall survival 19.4 months. A favorable outcome was seen in patients with the EGF61A/G genotype compared with the combined group of A/A and G/G, with response rates of 57% and 18%, respectively (P = 0.001). There was a significantly different progression-free survival (P = 0.018) in favor of the A/G group. The TS and ERCC1 genotypes failed to provide any significant impact on the outcome.ConclusionPolymorphism analysis of a simple blood sample is a feasible approach to biomarker analysis and the EGF61A>G polymorphism may influence the effect of first-line XELOX. Consequently, this marker deserves further investigation.     

Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer.

Cigarette smoking may induce DNA damage. Lower DNA repair capacities have been associated with higher risk of lung cancer. Excision repair cross-complementing group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process, and low expression of ERCC1 mRNA levels has been associated with higher risk of cancers. We examined the association between two polymorphisms of ERCC1, 8092C > A (rs3212986) and 19007T > C (codon 118, rs11615), which are associated with altered ERCC1 mRNA stability and mRNA levels, in 1,752 Caucasian lung cancer patients and 1,358 controls. The results were analyzed using logistic regression models, adjusting for relevant covariates. The two polymorphisms were in Hardy-Weinberg disequilibrium and in linkage disequilibrium. There was no overall association between ERCC1 polymorphisms and lung cancer risk, with the adjusted odds ratios (AOR) of 1.26 [95% confidence interval (95% CI), 0.81-1.96] for the 8092C > A polymorphism (A/A versus C/C) and 0.93 (95% CI, 0.67-1.30) for the 19007T > C polymorphism (C/C versus T/T). Stratified analyses revealed that the AORs for the 8092C > A polymorphism (A/A versus C/C) decreased significantly as pack-years increased, with the AOR of 2.11 (95% CI, 1.03-4.31) in never smokers and 0.50 (95% CI, 0.25-1.01) in heavy smokers (>/=56 pack-years), respectively. Consistent results were found when gene-smoking interaction was incorporated by joint effects and interactions models that considered both discrete and continuous variables for cumulative smoking exposure. The same direction for the gene-smoking interaction was found for the 19007T > C polymorphism, although the interaction was not statistically significant. In conclusion, ERCC1 8092C > A polymorphism may modify the associations between cumulative cigarette smoking and lung cancer risk.     

A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer

In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.     

ERCC1, MLH1, MSH2, MSH6, and βIII-Tubulin: Resistance Proteins Associated With Response and Outcome to Platinum-based Chemotherapy in Malignant Pleural Mesothelioma

IntroductionPlatinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for “tailoring” chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.Material and MethodsPre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.ResultsERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.ConclusionsEnzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.     

DNA repair gene polymorphisms and genetic predisposition to cutaneous melanoma

The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.