ERCC1和XRCC1基因多态性与接受奥沙利铂为基础新辅助化疗的进展期胃癌患者的疗效关系
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摘要
目的探讨切除修复交叉互补基因1(ERCC1)和X线修复交叉互补基因1(XRCC1)的单核苷酸基因多态性与接受奥沙利铂为基础新辅助化疗的进展期胃癌患者疗效的关系。方法选取收治的96例进展期胃癌患者并进行以奥沙利铂为基础的新辅助化疗治疗,采用限制性片段长度多态性聚合酶链反应(PCR-RFLP)技术检测ERCC1 Asn118Asn位点基因型和XRCC1 Arg194Trp位点基因型。分析ERCC1和XRCC1基因多态性与患者临床病理参数的关系,并观察ERCC1、XRCC1基因多态性与患者化疗有效率及无进展生存期(PFS)的关系。结果 96例进展期胃癌患者中ERCC1(47例)三种基因型分别为C/C 20例,C/T 23例,T/T 4例;XRCC1(49例)三种基因型分别为A/A 21例,A/T 23例,T/T 5例;二者基因型分布均符合Hardy-Weinberg遗传平衡定律。ERCC1不同基因型患者组织分化程度不同(P<0.05);XRCC1不同基因型患者TNM分期不同(P<0.05)。胃癌患者化疗的有效率及疾病控制率在ERCC1基因中以C/C型最高(P<0.05),在XRCC1基因中以A/T型最高(P<0.05)。将ERCC1与XRCC1基因中至少含有一个T碱基的等位基因型合并即(C/T+T/T)与(A/T+T/T),分析发现PFS无论在XRCC1中A/A型与(A/T+T/T)型患者间还是ERCC1中C/C型与(C/T+T/T)型患者间比较,差异均无统计学意义(P均>0.05);COX多元回归分析发现,ERCC1的C/C分别与XRCC1的A/A、(A/T+T/T)的联合基因型,以及ERCC1的C/T与XRCC1的A/A的联合基因型均是影响化疗效果的危险因素(P=0.042、0.023、0.017)。结论 ERCC1与XRCC1基因多态性分析或可用于预测接受以奥沙利铂为基础新辅助化疗的进展期胃癌患者的疗效,对二者基因多态性进行研究有助于为患者选择适合的个体化治疗方案。
Objective To investigate the relationship between gene polymorphisms of excision repair cross-complementing group 1(ERCC1),X-ray repair cross-complementing group 1(XRCC1)and the efficacy of oxaliplatin-based neoadjuvant chemotherapy for patients with advanced gastric cancer.Methods Ninety-six patients with advanced gastric cancer were selected and treated with oxaliplatin-based neoadjuvant chemotherapy.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)was used to detect genotyping of ERCC1(Asn118 Asn locus) and XRCC1(Arg194 Trp locus).The associations of polymorphisms of ERCC1 and XRCC1 with the clinicopathologic parameters,the effective rate of chemotherapy and progression-free survival(PFS)time were observed.Results Among 96 patients with advanced gastric cancer,ERCC1 genotypes were C/C(n=20),C/T(n=23) and T/T(n=4),XRCC1 genotypes were A/A(n=21),A/T(n=23) and T/T(n=5),respectively.The distribution of ERCC1 genotypes was in accordance with Hardy-Weinberg's law of genetic balance.The degree of tissue differentiation was different in patients with different genotypes of ERCC1(P<0.05),and the TNM stage was different in patients with different genotypes of XRCC1(P<0.05).The effective rate of chemotherapy and disease control rate of gastric cancer patients were the highest in ERCC1 C/C genotype(P< 0.05) and in XRCC1 A/T genotype(P<0.05).Combining of ERCC1 and XRCC1 alleles containing at least one T base into(C/T+T/T) and(A/T+T/T),it was found that there was no significant difference in PFS between genotype A/A and(A/T+T/T) patients in XRCC1 or between genotype C/C and(C/T+T/T) patients in ERCC1(all P>0.05).COX multivariate regression analysis showed that multiple combined genotypes [ERCC1 C/C with XRCC1 A/A,ERCC1 C/C with XRCC1(A/T+T/T);ERCC1 C/T with XRCC1 A/A]were risk factors affecting the efficacy of chemotherapy(P=0.042,0.023,0.017).Conclusion The gene polymorphisms of ERCC1 and XRCC1 may be served as the indicators evaluating efficacy of oxaliplatin-based neoadjuvant chemotherapy for patients with advanced gastric cancer.
Objective To investigate the relationship between gene polymorphisms of excision repair cross-complementing group 1(ERCC1),X-ray repair cross-complementing group 1(XRCC1)and the efficacy of oxaliplatin-based neoadjuvant chemotherapy for patients with advanced gastric cancer.Methods Ninety-six patients with advanced gastric cancer were selected and treated with oxaliplatin-based neoadjuvant chemotherapy.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)was used to detect genotyping of ERCC1(Asn118 Asn locus) and XRCC1(Arg194 Trp locus).The associations of polymorphisms of ERCC1 and XRCC1 with the clinicopathologic parameters,the effective rate of chemotherapy and progression-free survival(PFS)time were observed.Results Among 96 patients with advanced gastric cancer,ERCC1 genotypes were C/C(n=20),C/T(n=23) and T/T(n=4),XRCC1 genotypes were A/A(n=21),A/T(n=23) and T/T(n=5),respectively.The distribution of ERCC1 genotypes was in accordance with Hardy-Weinberg's law of genetic balance.The degree of tissue differentiation was different in patients with different genotypes of ERCC1(P<0.05),and the TNM stage was different in patients with different genotypes of XRCC1(P<0.05).The effective rate of chemotherapy and disease control rate of gastric cancer patients were the highest in ERCC1 C/C genotype(P< 0.05) and in XRCC1 A/T genotype(P<0.05).Combining of ERCC1 and XRCC1 alleles containing at least one T base into(C/T+T/T) and(A/T+T/T),it was found that there was no significant difference in PFS between genotype A/A and(A/T+T/T) patients in XRCC1 or between genotype C/C and(C/T+T/T) patients in ERCC1(all P>0.05).COX multivariate regression analysis showed that multiple combined genotypes [ERCC1 C/C with XRCC1 A/A,ERCC1 C/C with XRCC1(A/T+T/T);ERCC1 C/T with XRCC1 A/A]were risk factors affecting the efficacy of chemotherapy(P=0.042,0.023,0.017).Conclusion The gene polymorphisms of ERCC1 and XRCC1 may be served as the indicators evaluating efficacy of oxaliplatin-based neoadjuvant chemotherapy for patients with advanced gastric cancer.
引文
[1] Nie Y,Wu K,Yu J,et al.A global burden of gastric cancer:the major impact of China[J].Expert Rev Gastroenterol Hepatol,2017,11(7):651-661.
[2] 崔勇,张荣香,王福立,等.新辅助化疗联合术后同步放化疗治疗Ⅲ期胃癌的疗效分析[J].中国肿瘤临床,2016,43(17):747-752.
[3] Wang H,Hao H,Guo H,et al.Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China[J].J Cancer,2018,9(8):1371-1378.
[4] 孙慧,方岳雨,吉莲花,等.DNA修复基因多态性影响晚期胃癌卡培他滨联合奥沙利铂化疗的临床预后[J].现代肿瘤医学,2017,25(22):86-90.
[5] 唐磊.国际抗癌联盟及美国癌症联合会胃癌TNM分期系统(第8版)影像相关更新解读[J].中华放射学杂志,2017,51(8):636-637.
[6] Krajewski KM,Nishino M,Ramaiya NH,et al.RECIST 1.1 compared with RECIST 1.0 in patients with advanced renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy[J].AJR Am J Roentgenol,2015,204(3):W282-W288.
[7] 赵舞阳,王玉梅,崔檬,等.基于姑息预后指数(PPI)的晚期胃癌患者的生存分析[J].中国卫生统计,2017,34(6):900-903.
[8] 姚春梅,肖克源,马淑盟,等.进展期胃癌术后辅助放化疗与单纯化疗的比较[J].重庆医学,2016,45(17):2348-2351.
[9] 沈国杰,朱侃恺,邬一军,等.新辅助化疗联合胃癌根治术治疗进展期胃癌的临床疗效[J].中华消化外科杂志,2017,16(3):240-244.
[10] 万一元,惠红霞,王晓炜,等.卡培他滨或替吉奥联合奥沙利铂方案治疗进展期胃癌的疗效及安全性[J].中华肿瘤杂志,2016,38(1):28-34.
[11] 许凤杰,刘瑞斯,彪林海,等.抗癌药物奥沙利铂与DNA分子相互作用的研究[J].生物化学与生物物理进展,2016,43(7):684-690.
[12] Ambrosone CB,Hong CC,Goodwin PJ.Host factors and risk of breast cancer recurrence:genetic,epigenetic and biologic factors and breast cancer outcomes[J].Adv Exp Med Biol,2015,862:143-153.
[13] 钟兰,符生苗,谢贤和,等.XRCC1基因多态性对晚期胃癌患者化疗疗效及生存期的影响[J].中国药房,2017,28(14):1873-1876.
[14] Huang MY,Huang JJ,Huang CM,et al.Relationship between expression of proteins ERCC1,ERCC2,and XRCC1 and clinical outcomes in patients with rectal cancer treated with FOLFOX-based preoperative chemoradiotherapy[J].World J Surg,2017,41(11):2884-2897.
[15] Gentile F,Barakat KH,Tuszynski JA.Computational characterization of small molecules binding to the human XPF active site and virtual screening to identify potential new DNA repair inhibitors targeting the ERCC1-XPF endonuclease[J].Int J Mol Sci,2018,19(5):E1328.
[16] 韩高华,卢开进,许万松,等.XRCC1基因多态性对食管癌患者急性放射性肺损伤的影响[J].中华肿瘤防治杂志,2016,23(S2):123-124.
[17] 张和平,张栋,徐恩赐,等.ERCC1、XRCC1单核苷酸多态性与鼻咽癌放化疗敏感性的相关性研究[J].肿瘤学杂志,2017,23(1):40-44.
[18] 易善永,赵玲,郑琪,等.ERCC1、TYMS和TUBB3 mRNA表达对HER-2阴性晚期胃癌化疗疗效的影响[J].中国临床研究,2018,31(1):70-72.
[19] 孙江涛,原翔,宋开放,等.肺癌组织中切除修复交叉互补基因1和核糖核苷酸还原酶亚单位1表达水平与非小细胞肺癌患者的疗效和生存期的关系[J].新乡医学院学报,2017,34(4):270-274.
[20] 韩雪琼.晚期结直肠癌患者中ERCC1Asn118Asn (C/T)基因多态性与奥沙利铂化疗疗效相关性的Meta分析[D].南宁:广西医科大学,2015.
[21] 王小卫,陈建华,邓红玉,等.XRCC1单核苷酸多态性与铂类药物化疗对肺癌患者外周血细胞参数影响的相关性分析[J].实用预防医学,2016,23(11):1306-1310.
[22] 陈小军,何侠.中国人群XRCC1 Arg399Gln基因多态性与结直肠癌易感性关系的Meta分析[J].肿瘤学杂志,2017,23(2):87-91.
[2] 崔勇,张荣香,王福立,等.新辅助化疗联合术后同步放化疗治疗Ⅲ期胃癌的疗效分析[J].中国肿瘤临床,2016,43(17):747-752.
[3] Wang H,Hao H,Guo H,et al.Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China[J].J Cancer,2018,9(8):1371-1378.
[4] 孙慧,方岳雨,吉莲花,等.DNA修复基因多态性影响晚期胃癌卡培他滨联合奥沙利铂化疗的临床预后[J].现代肿瘤医学,2017,25(22):86-90.
[5] 唐磊.国际抗癌联盟及美国癌症联合会胃癌TNM分期系统(第8版)影像相关更新解读[J].中华放射学杂志,2017,51(8):636-637.
[6] Krajewski KM,Nishino M,Ramaiya NH,et al.RECIST 1.1 compared with RECIST 1.0 in patients with advanced renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy[J].AJR Am J Roentgenol,2015,204(3):W282-W288.
[7] 赵舞阳,王玉梅,崔檬,等.基于姑息预后指数(PPI)的晚期胃癌患者的生存分析[J].中国卫生统计,2017,34(6):900-903.
[8] 姚春梅,肖克源,马淑盟,等.进展期胃癌术后辅助放化疗与单纯化疗的比较[J].重庆医学,2016,45(17):2348-2351.
[9] 沈国杰,朱侃恺,邬一军,等.新辅助化疗联合胃癌根治术治疗进展期胃癌的临床疗效[J].中华消化外科杂志,2017,16(3):240-244.
[10] 万一元,惠红霞,王晓炜,等.卡培他滨或替吉奥联合奥沙利铂方案治疗进展期胃癌的疗效及安全性[J].中华肿瘤杂志,2016,38(1):28-34.
[11] 许凤杰,刘瑞斯,彪林海,等.抗癌药物奥沙利铂与DNA分子相互作用的研究[J].生物化学与生物物理进展,2016,43(7):684-690.
[12] Ambrosone CB,Hong CC,Goodwin PJ.Host factors and risk of breast cancer recurrence:genetic,epigenetic and biologic factors and breast cancer outcomes[J].Adv Exp Med Biol,2015,862:143-153.
[13] 钟兰,符生苗,谢贤和,等.XRCC1基因多态性对晚期胃癌患者化疗疗效及生存期的影响[J].中国药房,2017,28(14):1873-1876.
[14] Huang MY,Huang JJ,Huang CM,et al.Relationship between expression of proteins ERCC1,ERCC2,and XRCC1 and clinical outcomes in patients with rectal cancer treated with FOLFOX-based preoperative chemoradiotherapy[J].World J Surg,2017,41(11):2884-2897.
[15] Gentile F,Barakat KH,Tuszynski JA.Computational characterization of small molecules binding to the human XPF active site and virtual screening to identify potential new DNA repair inhibitors targeting the ERCC1-XPF endonuclease[J].Int J Mol Sci,2018,19(5):E1328.
[16] 韩高华,卢开进,许万松,等.XRCC1基因多态性对食管癌患者急性放射性肺损伤的影响[J].中华肿瘤防治杂志,2016,23(S2):123-124.
[17] 张和平,张栋,徐恩赐,等.ERCC1、XRCC1单核苷酸多态性与鼻咽癌放化疗敏感性的相关性研究[J].肿瘤学杂志,2017,23(1):40-44.
[18] 易善永,赵玲,郑琪,等.ERCC1、TYMS和TUBB3 mRNA表达对HER-2阴性晚期胃癌化疗疗效的影响[J].中国临床研究,2018,31(1):70-72.
[19] 孙江涛,原翔,宋开放,等.肺癌组织中切除修复交叉互补基因1和核糖核苷酸还原酶亚单位1表达水平与非小细胞肺癌患者的疗效和生存期的关系[J].新乡医学院学报,2017,34(4):270-274.
[20] 韩雪琼.晚期结直肠癌患者中ERCC1Asn118Asn (C/T)基因多态性与奥沙利铂化疗疗效相关性的Meta分析[D].南宁:广西医科大学,2015.
[21] 王小卫,陈建华,邓红玉,等.XRCC1单核苷酸多态性与铂类药物化疗对肺癌患者外周血细胞参数影响的相关性分析[J].实用预防医学,2016,23(11):1306-1310.
[22] 陈小军,何侠.中国人群XRCC1 Arg399Gln基因多态性与结直肠癌易感性关系的Meta分析[J].肿瘤学杂志,2017,23(2):87-91.