ERCC2/XPD和XRCC1基因多态性与鼻咽癌放化疗患者临床转归的相关性研究

Correlation study between ERCC2/XPD and XRCC1 gene polymorphism and clinical outcomes of radiotherapy and chemotherapy for patients with nasopharyngeal carcinoma

目的探讨D组着色性干皮病偶联因子(XPD)的核苷酸切除修复交叉互补基因2(ERCC2/XPD) Lys751Gln和XRCC1 Arg194Trp基因多态性与鼻咽癌(NPC)患者放化疗敏感性及预后相关性。方法选择2015年1月至2016年12月在海南医学院第一附属医院首次接受治疗的NPC患者128例,其中男性82例,女性46例;年龄35~77岁,平均年龄56.28岁。根据放化疗是否敏感分为敏感组和不敏感组。记录所有患者临床资料。采用聚合酶链反应(PCR)检测2组患者ERCC2/XPD Lys751Gln和XRCC1 Arg194Trp基因多态性,采用Hardy-Weinberg遗传平衡吻合度检验法计算各基因型的理论值。Logistic回归分析影响NPC放化疗敏感性的因素,Kaplan-Meier分析不同基因型组间总生存期(OS)的差异。结果敏感组72例,不敏感组56例。敏感组与不敏感组性别、年龄、吸烟习惯、Karnofsky(KPS)评分、化疗方式、T分期比较,差异无统计学意义(P> 0.05),两组患者N分期、美国癌症联合委员会(AJCC)分期、分化程度、淋巴结转移比例、放疗前肿瘤靶区体积(GTVnx)及淋巴结靶区体积(GTVnd)差异有统计学意义(P <0.05);两组间ERCC2/XPD Lys751Gln和XRCC1 Arg194Trp的3种基因型均符合Hardy-Weinberg遗传平衡定律(P> 0.05);两组患者ERCC2/XPD Lys751Gln基因和XRCC1 Arg194Trp基因的不同基因型分布比较,差异有统计学意义(P <0.05);多因素Logistic回归分析显示,N分期N2+N3期、放疗前GTVnx、放疗前GTVnd、淋巴结转移及ERCC2/XPD Lys751Gln的携带Gln基因型和XRCC1Arg194Trp的携带Trp基因型是影响NPC患者放化疗的独立危险因素;携带ERCC2/XPD Lys751Gln基因Gln等位基因患者3年OS为60.00%,不携带Gln等位基因患者3年OS为79.17%,两者差异具有统计学意义(P <0.05);携带XRCC1 Arg194Trp基因Trp等位基因患者3年OS为58.14%,不携带Trp等位基因患者3年OS为73.81%,两者差异具有统计学意义(P <0.05)。结论 ERCC2/XPD Lys751Gln和XRCC1 Arg194Trp基因多态性与NPC患者放化疗敏感性有关,分别携带Gln、Trp等位基因是放化疗敏感性的危险因素,且患者OS明显降低。

Objective To investigate the correlation between nucleotide excision repair cross complementary gene 2(ERCC2/XPD) Lys751 Gln and XRCC1 Arg194 Trp gene polymorphisms and chemoradiotherapy sensitivity and prognosis in patients with nasopharyngeal carcinoma(NPC). Methods From January 2015 to December 2016, a total of 128 NPC patients were enrolled,which included 82 males and 46 females, aged 35-77 years old with mean age of 56.28 years old. According to sensitivity of radiotherapy and chemotherapy, all of the patients were divided into sensitive group and insensitive group. The clinical data of all patients were recorded. The polymerase chain reaction(PCR) was used to detect gene polymorphisms of ERCC2/XPD Lys751 Gln and XRCC1 Arg194 Trp of 2 groups, and theoretical value of each genotype was calculated by Hardy-Weinberg genetic balance agreement test. The Logistic regression was used to analyze factors affected sensitivity of radiotherapy and chemotherapy for NPC, and Kaplan-Meier analysis was used to analyze the difference of overall survival(OS) among different genotypes. Results There were no statistically significant differences between sensitive group(n = 72) and insensitive group(n = 56) in gender, age, smoking habits, Karnofsky(KPS) score, chemotherapy method and T-staging(P > 0.05). There were statistically significant differences in N-staging, American Joint Committee on Cancer(AJCC) staging, differentiation degree, proportion of lymph node metastasis, gross tumor volume(GTVnx) and lymph node gross tumor volume(GTVnd) before radiotherapy between 2 groups(P < 0.05). The three genotypes of ERCC2/XPD Lys751 Gln and XRCC1 Arg194 Trp between 2 groups were consistent with Hardy-Weinberg genetic equilibrium law(P > 0.05). The differences in distribution of ERCC2/XPD Lys751 Gln gene and XRCC1 Arg194 Trp gene between 2 groups were statistically significant(P < 0.05). The multivariate Logistic regression analysis showed that N-staging N2 + N3, GTVnx and GTVnd before radiotherapy, lymph node metastasis, ERCC2/XPD Lys751 Gln genotype and XRCC1 Arg194 Trp genotype were independent risk factors for radiotherapy and chemotherapy in NPC patients. The 3-year OS of patients with Gln allele of ERCC2/XPD Lys751 Gln gene was 60.00 %, and 79.17 % without Gln alleles, and the difference was statistically significant(P < 0.05). The 3-year OS of the patients with Trp allele of XRCC1 Arg194 Trp gene was 58.14 %, and 73.81 % without Trp allele, and the difference was statistically significant(P < 0.05). Conclusion It is demonstrated that ERCC2/XPD Lys751 Gln and XRCC1 Arg194 Trp polymorphisms are correlated with chemoradiosensitivity in patients with NPC, carrying Gln or Trp alleles are risk factors for radiochemotherapy sensitivity, and OS is significantly reduced.