ERCC1和XPD单核苷酸多态性与非小细胞肺癌铂类化疗敏感性的关系

目的：探讨DNA修复基因ERCC1 C118T和XPD Lys751Gln单核苷酸多态性与非小细胞肺癌（non-small-cell lung carcinoma,NSCLC）患者对含铂方案化疗敏感性的关系。方法：选择经病理确诊为NSCLC的患者73例,在实施化疗前采取静脉血,提取DNA,行DNA测序、用PCR-RFLP方法检测ERCC1 C118T和XPD Lys751Gln基因型。所有患者均经含铂方案化疗,观察疗效,统计临床获益率,分析NSCLC患者ERCC1和XPD单核苷酸多态性与含铂方案化疗敏感性的关系。结果：ERCC1 C118TC/C、C/T和T/T基因型临床获益率分别为94.9%、71.4%和83.8%。基因型C/C临床获益率明显高于C/T、T/T（P〈0.05）。XPD Lys751Gln基因型Lys/Lys、Lys/Gln临床获益率分别为80.3%和75.0%。基因型Lys/Lys与Lys/Gln临床获益率间的差异无统计学意义（P=0.702）。未检测到XPD Gln/Gln基因型。ERCC1 C118T、XPD Lys751Gln多态之间在对含铂方案的化疗敏感性方面无协同作用（P=0.134和P=0.236）。结论：DNA修复基因ERCC1 C118T单核苷酸多态性与NSCLC含铂方案化疗的敏感性有关,可作为预测NSCLC患者铂类药物化疗敏感性的参考指标之一。     

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.     

DNA repair gene ERCC1 and XPD polymorphisms predict glioma susceptibility and prognosis

Aims: We conducted a case-control study in a Chinese population to clarify the association betweenpolymorphisms in ERCC1 and XPD and susceptibility and survival of glioma. Methods: A total of 393 cases and410 controls were selected from March 2007 to December 2011. Genotyping of ERCC1 and XPD was conductedby TaqMan assays using the ABI Prism 7911HT Sequence Detection System. All analyses were performed usingthe STATA statistical package. Results: Polymorphisms in ERCC1 118C/T, ERCC1 8092C/A and XPD Asp312Asnshowed no statistically significant difference between glioma cases and controls. However, individuals with theXPD 751Gln/Gln genotype had an increased risk of developing glioma compared with those with the Lys/Lysgenotype (adjusted OR=1.64, 95% CI: 1.06-2.89). The ERCC1 118T/T genotype was associated with significantlyhigher median survival than the ERCC1 C/C genotype (HR=0.67, 95%CI=0.35-0.96). In addition, individualswith XPD 751Gln/Gln had a lower median survival time than XPD Lys/Lys carriers (HR=0.54, 95%CI=0.37-0.93). Conclusion: In conclusion, we observed that the XPD 751Gln/Gln genotype is associated with gliomasusceptibility, and ERCC1 118 T/T and XPD 751Gln/Gln genotypes confer a significantly better prognosis.     

The ERCC1 C118T Polymorphism Predicts Clinical Outcomes of Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy: a Meta-analysis Based on 22 Studies

Background: Although the predictive value of the excision repair cross-complementing group 1 (ERCC1)C118T polymorphism in clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-basedchemotherapy has been evaluated in numerous published studies, the conclusions are conflicting. Therefore, weperformed the present meta-analysis to determine the precise role of the ERCC1 C118T polymorphism in thisclinical situation and help optimize individual chemotherapy. Materials and Methods: A multiple search strategywas used to identify eligible studies. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) wereused to estimate objective response and oxaliplatin-induced toxicity, with hazard ratios (HRs) with 95%CIs forprogression-free survival (PFS) and overall survival (OS). Results: A total of 22 studies including 2,846 CRCpatients were eligible in the analysis. Overall, no significant correlation was found between the ERCC1 C118Tpolymorphism and objective response to oxaliplatin-based chemotherapy, in all patients or in the Asian andCaucasian subgroups. However, the pooled analysis showed that the PFS and OS were significantly shorter inpatients who carried T/T or T/C genotypes of ERCC1 C118T as compared to the C/C genotype. On stratifiedanalysis by ethnicity, the ERCC1 118T allele was associated with a favorable prognosis in Caucasians (PFS,HR=0.58, 95%CI: 0.24-1.44; OS, HR=0.38, 95%CI: 0.22-0.64) but an unfavorable prognosis in Asians (PFS,HR=2.49, 95%CI: 1.87-3.33; OS, HR=2.63, 95%CI: 1.87-3.69) based on a dominant model. In addition, wefailed to find a statistically significant impact of ERCC1 C118T polymorphism on oxaliplatin-induced toxicity.Conclusions: The ERCC1 C118T polymorphism may have prognostic value in patients with CRC undergoingoxaliplatin-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.     

The XPD Lys751Gln Polymorphism has Predictive Value in Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy: a Systemic Review and Meta-analysis

Background: The predictive value of the xeroderma pigmentosum group D (XPD) Lys751Gln polymorphismregarding clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-based chemotherapyhas been evaluated in numerous published studies, but the results remain inconclusive. Therefore, we performeda meta-analysis to determine the precise role of the XPD Lys751Gln polymorphism in this clinical situation andoptimize individual chemotherapy. Materials and Methods: A multiple search strategy was used to identify eligiblestudies. Pooled odds ratios (ORs), generalized odds ratio (ORG) and their 95% confidence intervals (CIs) wereused to estimate the objective response, while hazard ratios (HRs) with 95%CIs were used for progression-freesurvival (PFS) and overall survival (OS). Results: A total of 17 studies including 2,286 patients met the inclusioncriteria. Overall, the XPD 751Gln allele was associated with a non-significant reduced objective response tooxaliplatin-based chemotherapy in all patients or in the Asian and Caucasian subgroups. However, poor PFSand OS of CRC patients treated with oxaliplatin-based regimens were significantly related to the XPD 751Glnallele in the dominant model (PFS: HR=2.10, 95%CI: 1.65-2.67; OS: HR=3.18, 95%CI: 1.57-6.47). On stratifiedanalysis by ethnicity, these relationships were more pronounced in Asians (PFS: HR=2.49, 95%CI: 1.79-3.47;OS: HR=5.25, 95%CI: 3.46-7.94) than in Caucasians (PFS: HR=1.73, 95%CI: 1.22-2.46; OS: HR=1.78, 95%CI:1.06-2.99). Conclusions: The XPD Lys751Gln polymorphism may have prognostic value in patients with CRCundergoing oxaliplatin-based chemotherapy.     

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.     

Impact of gene polymorphisms on clinical outcome for stage IV melanoma patients treated with biochemotherapy: an exploratory study.

PURPOSE: Biochemotherapy can achieve high response rates in advanced melanoma, but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis that cytokine gene polymorphisms predict clinical outcome in stage IV melanoma patients treated with biochemotherapy. EXPERIMENTAL DESIGN: Ninety patients with stage IV melanoma were treated with biochemotherapy, including cisplatin, vinblastine, and dacarbazine combined with interleukin (IL)-2 and IFN-alpha either with or without tamoxifen. Cytokine gene polymorphisms for IFN-gamma (+874A-->T) and IL-10 (-1082G-->A) were assessed. X-ray repair cross-complementing gene 1 (XRCC1; Arg399Gln), xeroderma pigmentosum complementary group D (XPD; Lys751Gln), and excision repair cross-complementing gene 1 (ERCC1; codon 118) DNA repair polymorphisms were also determined. RESULTS: IFN-gamma (+874A-->T) gene polymorphism was statistically significantly associated with response (P = 0.001), progression-free survival (P = 0.0012), and overall survival (P < 0.001), whereas the IL-10 polymorphism was marginally associated with response (P = 0.03) and overall survival (P = 0.065). Multivariate analysis revealed that IFN-gamma (+874A-->T) independently predicted overall survival (P = 0.003). The ERCC1 polymorphism was weakly associated with overall survival (P = 0.045). Combining polymorphisms for IFN-gamma, IL-10, and ERCC1 stratified patients into four distinct groups with significantly different clinical outcome (P < 0.001), so that patients with more "favorable" polymorphisms had a better outcome. CONCLUSIONS: Cytokine gene polymorphisms predicted clinical outcome for advanced melanoma patients who received biochemotherapy. The combined effects of multiple genetic polymorphisms may provide more accurate prognostic information. Additional independent studies are needed to confirm these pilot findings.     

The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis

The relationship between the ERCC1/2 single nucleotide polymorphisms (SNPs) and the clinical outcomes of the platinum-based chemotherapy in the non-small cell lung cancer (NSCLC) is still inconsistent and inconclusive despite extensive investigations have been conducted to address this question. In this meta-analysis, we aim to further explore the prognostic value of the ERCC1/2 SNPs in NSCLC by analyzing all currently available evidences. Relevant studies were searched in PubMed, Embase, and China National Knowledge Infrastructure. The inclusion criteria were platinum-based chemotherapy in NSCLC patients and evaluation of clinical outcomes in relation to the ERCC1 C118T, ERCC1 C8092A, ERCC2 Asp312Asn, and ERCC2 Lys751Gln. Clinical outcomes analyzed in this study included the overall response rate, overall survival (OS), and progression-free survival (PFS). Odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (CI) were calculated to examine the risk or hazard associated with each SNP. A total of 46 studies including 9,407 NSCLC patients were qualified for this meta-analysis. For ERCC1 C118T, the T allele was associated with a poor OS (HR?=?1.35, 95 % CI?=?1.04–1.75); for ERCC2 Asp312Asn, the Asn variant was linked to an unfavorable OS (HR?=?2.07, 95 % CI?=?1.11–3.88); and for ERCC2 Lys751Gln, patients with the Gln variant have a worse OS (HR?=?1.22, 95 % CI?=?1.05–1.41) and PFS (HR?=?1.35, 95 % CI?=?1.07–1.71). In addition, the main findings of the ERCC1/2 SNPs on chemotherapy toxicity were also summarized. This meta-analysis suggested that the ERCC1 C118T, ERCC2 Asp312Asn, and Lys751Gln may be useful biomarkers to predict the clinical outcomes of the platinum-based chemotherapy in NSCLC patients.     

Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer.

BACKGROUND: Mucinous carcinoma of the colon and rectum (mucinous CRC) is a histological subtype of colorectal adenocarcinoma for which there is little data on chemotherapy responsiveness. The purpose of this study was to investigate specifically the efficacy of fluorouracil-based first-line chemotherapy in patients with advanced mucinous CRC. PATIENTS AND METHODS: All patients with advanced mucinous CRC enrolled in three prospective randomized trials evaluating infused 5-fluorouracil as first-line treatment were compared with patients with non-mucinous subtypes enrolled in the same trials in a case-control study. Prognostic factors associated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. RESULTS: The study included 135 patients (45 cases and 90 controls). The response rates for cases and controls were 22% [95% confidence interval (CI), 11% to 38%] and 47% (95% CI, 36.1% to 58.2%), respectively (P=0.0058). Median OS for the mucinous CRC patients was 11.8 months (95% CI, 8.87-14.8) compared with 17.9 months (95% CI, 13.38-22.39) in the control group (univariate analysis, P=0.056); after correcting for significant prognostic factors by multivariate Cox regression analysis, P=0.0372 and hazard ratio (HR)=1.497 (1.02-2.19). CONCLUSION: Patients with advanced mucinous CRC have a poorer response to fluorouracil-based first-line chemotherapy and reduced survival compared with patients with non-mucinous CRC.     

Predictive role of ERCC1 and XPD genetic polymorphisms in survival of Chinese non-small cell lung cancer patients receiving chemotherapy

Aim: There is increasing evidence that ERCC1 and XPD have roles in response to chemotherapy amongpatients with NSCLC, but the results are conflicting. Therefore, we conducted the present prospective study ina Chinese population. Methods: A total of 632 primary NSCLC patients were included, followed-up from May2006 to May 2011. Polymorphisms were detected by real time PCR with TaqMan probse, using genomic DNAextracted from peripheral blood samples. The Cox regression model was used to analyze the hazard ratios (HR)for ERCC1 and XPD. Results: The median time of follow-up was 31.6 months. Our results showed the ERCC1118 T/T(HR=1.65, 95% CI=1.17-2.43) and XPD 751 Gln/ Gln genotypes (HR=1.52, 95%CI=1.04-2.08) wereassociated with an increased risk of death from NSCLC. Moreover, the ERCC118 T allele and XPD 751 Glnallele genotypes had a more higher risk of death from NSCLC among both ex-smokers and current smokers.Conclusion: In summary, ERCC1 and XPD gene polymorphisms might provide better prognostic predictiveinformation for NSCLC patients in Chinese populations, with smoking possibly interacting with the genotypes.     

Association of Four ERCC1 and ERCC2 SNPs with Survival of Bone Tumour Patients

Aim: SNPs of ERCC1 and ERCC2 genes have been found to be associated with response to platinum therapyin different clinical settings. In the current study, we investigated the relationship of SNPs in ERCC1 and ERCC2to cisplain response and survival in osteosarcoma patients. Methods: 267 consecutive patients diagnosed withosteosarcoma between January 2003 to January 2005 were followed up until the end of January 2010. ERCC1Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln polymorphisms were detectedbased upon the Sequenom MassARRAY platform. Results: For ERCC1 Asn118Asn, the variant genotype T/Twas strongly significantly associated with a higher event free survival when compared with the wild-type C/C,with an adjusted OR (95% CI) of 0.39 (0.14-0.95). ERCC2 751 A/A genotype showed increased event free survivalof osteosarcoma (HR=0.44; 95%CI=0.10-0.87). However, we did not find significant association of ERCC1Gln504Lys and ERCC2 Asp312Asn polymorphisms with prognosis of osteosarcoma. Conclusion: We first reportassociations of four SNPs, ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln,with risk of death from osteosarcoma in a Chinese population, indicating ERCC1 118T/T and ERCC2 A/A maybe used as surrogate markers for clinical outcome of osteosarcoma treatmetn with cisplain.     

切除修复交叉互补基因1和X线修复交叉互补基因1及谷胱甘肽巯基转移酶π 1多态性与晚期胃癌患者生存期的关系

目的 探讨切除修复交叉互补基因1(ERCC1)、X线修复交叉互补基因1(XRCC1)和谷胱甘肽巯基转移酶π1(GSTP1)多态性与中国晚期胃癌患者接受含奥沙利铂方案一线化疗后生存期的关系.方法 85例晚期胃癌患者接受奥沙利铂+5-氟尿嘧啶为基础的联合化疗方案化疗,并在化疗前抽取患者静脉血,提取基因组DNA,以实时荧光定量PCR法行多态性检测,比较不同基因型与患者生存期的关系.结果 85例患者中位至疾病进展时间为5.3个月,中位生存期为8.0个月.ERCC1-118 C/C、XRCC1-399 G/G和GSTP1-105 A/G+G/G基因型为优势基因型,携带3个、2个、1个、0个优势基因型患者的中位生存期分别为12.5、10.0,6.5和4.5个月,组间差异有统计学意义(χ2=35.54,P<0.01).结论 ERCC1-118、XRCC1-399和GSTP1-105基因多态性与中国晚期胃癌患者接受含奥沙利铂化疗方案一线化疗后的生存期相关,可预测患者的预后.     

No evidence of an association of ERCC1 and ERCC2 polymorphisms with clinical outcomes of platinum-based chemotherapies in non-small cell lung cancer: a meta-analysis

Background

The nucleotide excision repair (NER) pathway modulates platinum-based chemotherapeutic efficacy by removing drug-induced DNA damage.

Methods

To summarize published data on the association between NER genes and responses to platinum-based chemotherapies in non-small cell lung cancer (NSCLC), we performed a meta-analysis of 17 published studies of ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms, including 2097 cancer patients. Primary outcomes included objective response (TR) (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). We calculated odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) to estimate the risk or hazard.

Results

We found that none of the ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms alone was statistically significantly associated with objective response, PFS and OS in NSCLC patients.

Conclusion

There is no evidence to support the use of NER ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC.     

核苷酸切除修复系统基因遗传多态与晚期非小细胞肺癌患者铂类药物敏感性关系

背景与目的:肿瘤细胞对铂类药物的化疗敏感性与个体的DNA损伤修复能力关系密切,本研究探讨核苷酸切除修复系统(nucleotideexcisionrepair,NER)的重要成员XPC、XPD和ERCC1基因的遗传多态与晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)患者对铂类药物敏感性的关系。方法:对接受含铂类药物化疗的200例晚期NSCLC患者进行临床疗效评价。以聚合酶链-扩增片段长度多态性(PCR-AFLP)和限制性片段长度多态性(RFLP)的方法检测XPC-PAT、XPDLys751Gln(rs1052559)和ERCC1C8092A(rs1052559)多态的基因型,比较不同基因型与化疗敏感性的关系。结果:结合疗效情况,XPC-PAT遗传多态各基因型在化疗有效组(CR PR)和无效组(SD PD)中的分布频率差异有显著性(!2检验,P=0.023),携带XPCLL基因型个体的化疗敏感性是XPCSS基因型携带者的3.04倍(95%CI为1.25～7.41,P=0.015)。没有发现XPDLys751Gln和ERCC1C8092A多态与化疗敏感性的相关性。但联合分析后发现,核苷酸切除修复系统的这三个遗传多态在晚期NSCLC患者对铂类药物敏感性中存在一定的联合作用(趋势检验,P=0.021)。结论:核苷酸切除修复系统中XPC-PAT、XPDLys751Gln和ERCC1C8092A遗传多态可能与NSCLC患者对铂类药物敏感性相关。     

结直肠癌基因XPD751和XPD312单核苷酸多态性与FOLFOX方案疗效相关性分析

目的探讨DNA修复基因XPD751和XPD312单核苷酸多态性与FOLFOX方案治疗中国晚期结直肠癌患者疗效的相关性;探讨两种基因单核苷酸多态性在晚期结直肠癌患者预后评估中的预测价值。方法收集2008-01-01-2013-12-31我院经病理学确诊并接受FOLFOX方案治疗的晚期结直肠癌76例患者,采集患者化疗前外周静脉血,经DNA提取后采用限制性片段长度多态性聚合酶链反应（RFLP-PCR）技术检测XPD751和XPD312的单核苷酸多态性,比较不同基因型与化疗疗效及预后的相关性。结果 XPD751野生型和突变型的分布频度分别为76.3%和23.7%,XPD312野生型和突变型的分布频度分别为55.3%和44.7%;XPD751野生型组和突变型组的疾病控制率（DCR）分别为79.3%和77.7%,XPD312分别为64.2%和79.4%,XPD751野生型患者化疗有效率优于突变型患者,χ^2=5.141,P=0.007;Logistic回归分析显示,携带XPD751野生型患者接受FOLFOX方案化疗的敏感性是携带突变型患者的3.5倍,OR=3.500,P=0.015。XPD312野生型组和突变型组化疗疗效差异无统计学意义,χ^2=2.456,P=0.483。XPD751野生型和突变型的中位无进展生存期（PFS）分别为9.96和7.8个月,XPD312分别为9.88和8.41个月。XPD751两类基因型的中位PFS差异有统计学意义,χ^2=11.769,P=0.001;XPD312两类基因型的中位PFS差异无统计学意义,χ^2=1.479,P〉0.05。同时携带XPD751野生型和XPD312野生型的PFS为12.95个月,同时携带XPD751野生型和XPD312突变型的PFS为8.36个月,同时携带XPD751突变型和XPD312野生型的PFS为7.8个月,同时携带XPD751突变型和XPD312突变型的PFS为7.14个月,组间差异有统计学意义,χ^2=12.722,P=0.005。Cox回归分析性别、年龄、肿瘤转移部位及上述四类基因分型与PFS的相关性显示,只有基因分型与PFS相关,P〈0.001,RR=1.445;分析上述四类基因分型,只有同时携带XPD751野生型和XPD312野生型的基因分型与PFS相关,P=0.006,RR=0.357。结论DNA修复基因XPD751单     

GSTP1, ERCC1 and ERCC2 Polymorphisms,Expression and Clinical Outcome of Oxaliplatin-based Adjuvant Chemotherapy in Colorectal Cancer in Chinese Population

Aim: Platinum agents have shown to be effective in the treatment of colorectal cancer. We assessed whethersingle nucleotide polymorphisms (SNPs) in GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln might predictthe overall survival in patients receiving oxaliplatin-based chemotherapy in a Chinese population. Methods:SNPs of GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln in 335 colorectal cancer patients were assessedusing TaqMan nuclease assays. Results: At the time of final analysis on Nov. 2011, the median follow-up periodwas 37.7 months (range from 1 to 60 months). A total of 229 patients died during follow-up. Our study showedGSTP1 Val/Val (HR=0.44, 95% CI=0.18-0.98), ERCC1 C/C (HR=0.20, 95% CI=0.10-0.79) and ERCC2 G/G(HR=0.48, 95% CI=0.19-0.97) to be significantly associated with better survival of colorectal cancer. GSTP1Val/Val, ERCC1 C/C and ERCC2 G/G were also related to longer survival among patients with colon cancer,with HRs (95% CIs) of 0.41 (0.16-0.91), 0.16 (0.09-0.74) and 0.34 (0.16-0.91), respectively. Conclusion: GSTP1,GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln genotyping might facilitate tailored oxaliplatin-basedchemotherapy for colorectal cancer patients.     

MTHFR和ABCG2单核苷酸多态性对晚期结直肠癌—线化疗疗效的预测作用

目的:探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)和乳腺癌耐药蛋白(breast cancer resistance protein,BCRP/ABCG2)基因单核苷酸多态性(single nucleotide polymorphism,SNP)对晚期结直肠癌一线化疗疗效的预测作用.方法:采用基因测序法检测154例接受FOLFOX、XELOX或FOLFIRI方案一线化疗的晚期结直肠癌患者外周血MTHFR 677C＞T、MTHFR 1298A＞C、ABCG2 34G＞A和ABCG2 421C＞A这4个位点的SNP,结合临床特征,分析其与近期疗效、无进展生存(progression-free survival,PFS)和总生存(overall survival,OS)之间的关系.结果:154例患者接受一线化疗的有效率为31.8％,中位PFS为8.1个月,中位OS为30.7个月.MTHFR和ABCG2 SNP与近期疗效和OS无显著相关性(P＞0.05).含3～4个优势基因型(MTHFR 677C/C、MTHFR 1298A/A、ABCG2 34G/A或A/A及ABCG2 421C/A或A/A)患者的中位PFS较含0～2个优势基因型患者的显著延长(分别为9.8和7.5个月,P=0.013).COX多因素分析结果显示,优势基因型数目(P=0.017)和原发灶是否根治切除(P=0.010)是影响PFS的独立因素.单因素和多因素分析结果均显示,原发灶是否根治切除是影响OS的独立因素(P=0.000,P=0.000).结论:联合分析MTHFR和ABCG2 SNP对一线化疗治疗晚期结直肠癌的PFS有一定的预测作用,原发灶是否根治切除是影响PFS和OS的独立因素.     

含吉西他滨方案和CHOP样方案一线治疗结外NK/T细胞淋巴瘤效果观察

目的 比较含吉西他滨的联合方案和CHOP样联合方案一线治疗结外NK/T细胞淋巴瘤的效果及安全性.方法 回顾性分析河南省人民医院2012年3月至2017年3月39例初治结外NK/T细胞淋巴瘤患者,其中11例采用含吉西他滨联合方案,28例采用CHOP样联合方案.比较两组的完全缓解(CR)率、部分缓解(PR)率、总反应率(ORR)、总生存(OS)率、无进展生存(PFS)率及不良反应.结果吉西他滨组CR 5例,PR 3例;CHOP样组CR 8例,PR 5例;两组CR率和ORR比较,差异均无统计学意义(P=0.453,P=0.073);两组预计3年OS率(75%比33%)、3年PFS率(70%比29%)比较,差异均有统计学意义(χ2=5.606,P=0.018;χ2=3.924,P=0.048).单因素分析结果显示,治疗方案(P=0.018)、乳酸脱氢酶(LDH)升高(P=0.007)影响患者生存预后(均P<0.05).多因素分析结果显示,LDH升高增加患者的死亡风险(RR=6.331,95%CI2.339~17.136,P<0.001),采用含吉西他滨方案治疗降低患者的死亡风险(RR=0.101,95%CI0.023~0.452,P=0.003).不良反应多为1~2级,患者耐受性良好.结论 含吉西他滨联合方案较CHOP样联合方案可延长结外NK/T细胞淋巴瘤患者的生存时间,提高远期疗效.