ERCC1 C118T基因多态性与晚期膀胱癌铂类方案化疗敏感性的研究

发布时间：2018-10-08 13:17

【摘要】：研究背景和目的：膀胱癌是我国泌尿外科临床上最常见的肿瘤之一,是一种直接威胁患者生存的疾病。晚期膀胱癌的治疗仍难以令人满意。顺铂联合吉西他滨(GC)的化疗方案可明显延长患者的总生存期,且不良反应少,因此被推荐为晚期膀胱癌的一线化疗方案。尽管如此,仍只有不足50%的患者对该化疗方案敏感。因此,寻找可预测晚期膀胱癌患者GC方案化疗敏感的分子标志物具有十分重要的临床意义。铂类药物例如顺铂是一种重金属络合物,可直接作用于DNA,与DNA形成加合物,限制DNA的解旋从而有效的抑制DNA的复制、转录。切除修复交叉互补基因1,简称ERCCl,是一种在核苷酸切除修复通路(NER)中的关键基因,在对损伤DNA的识别及修复起着至关重要的作用。ECCCl基因高表达在局部进展期膀胱癌顺铂为主的辅助化疗中是不良的预后因素。到目前为止,关于ERCClC118T基因多态性与晚期膀胱癌铂类方案化疗敏感性的研究仍没有相关报道。因此我们开展了一项非随机,回顾性研究调查其在膀胱癌化疗中的作用。方法：选择2010年1月至2012年9月江苏省肿瘤医院收治的经病例组织学确认的晚期膀胱癌患者41例,接受顺铂联合吉西他滨方案化疗2-6周期。采用PCR-RFLP检测ERCCl codon118基因型,采用RECIST评分评价化疗后效果,CR+PR为有效,SD+PD为无效。比较不同基因型及各种临床病理特点与铂类方案化疗后生存期的关系。结果：ERCCl codon 118携带野生型C/C占56.1%(23/41), 杂合性C/T占34.1%(14/41),突变型T/T占9.8%(4/41)。携带ERCCl codon 118 C/C基因型的PFS为6个月,而携带C/T或T/T基因型的为4个月(χ2=5.154,p=0.032)。此外,携带ERCCl codon 118 C/C基因型的OS也较携带C/T或T/T基因型的明显延长(11个月对8个月,妒=4.199,p=0.040)。在对影响PFS及OS预后的多因素回归分析中,携带ERCCl codon 118 C/C野生型是携带C/T杂合型的1.83倍(P=0.016,HR=1.83,95%CI=1.12-2.99),是携带ERCCl codon 118 T/T突变型的1.94倍(P=0.010,HR:1.94,95%CI=1.17-3.27)。结论：携带ERCCl codon 118C/C基因型比其他基因型相比,有更好的化疗客观反应率,且明显延长PFS及总OS.ERCCl codon 118 C/C可能成为预测晚期膀胱癌化疗敏感性的关键分子标志物。
[Abstract]:Background and objective: bladder cancer is one of the most common tumors in urology in China. The treatment of advanced bladder cancer is still unsatisfactory. Cisplatin combined with gemcitabine (GC) regimen can significantly prolong the overall survival of patients with less adverse reactions, so it is recommended as a first-line chemotherapy regimen for advanced bladder cancer. Still, less than 50% of patients are sensitive to the regimen. Therefore, it is of great clinical significance to search for molecular markers that can predict the chemosensitivity of GC regimen in patients with advanced bladder cancer. Platinum, such as cisplatin, is a heavy metal complex that acts directly on DNA, and DNA to form adducts, limiting the unwinding of DNA and effectively inhibiting the replication and transcription of DNA. Excision repair cross-complementary gene 1 (ERCCl,) is a key gene in nucleotide excision repair pathway (NER). ECCCL gene overexpression is a poor prognostic factor in cisplatin-based adjuvant chemotherapy for local advanced bladder cancer. Up to now, there has been no report on the relationship between ERCClC118T gene polymorphism and chemotherapy sensitivity of platinum regimen in advanced bladder cancer. Therefore, we conducted a non-random, retrospective study to investigate its role in bladder cancer chemotherapy. Methods: 41 patients with advanced bladder cancer admitted to Jiangsu Cancer Hospital from January 2010 to September 2012 were treated with cisplatin combined with gemcitabine regimen for 2-6 cycles. ERCCl codon118 genotypes were detected by PCR-RFLP, and RECIST score was used to evaluate the effect of chemotherapy. The CR PR was effective and SD PD was ineffective. To compare the relationship between different genotypes and clinicopathological features and survival time after chemotherapy with platinum regimen. Results the percentage of wild type C / C was 56.1% (23 / 41), heterozygosity C / T was 34.1% (14 / 41) and mutant T / T was 9.8% (4 / 41). The PFS with ERCCl codon 118C / C genotype was 6 months, while the PFS with C / T or T / T genotype was 4 months (蠂 ~ 2 / 5.154P ~ (0.032). In addition, OS with ERCCl codon 118C / C genotype was significantly longer than that with C / T or T / T genotype (11 months vs 8 months, 4.199p0.040). In multivariate regression analysis of the prognosis of PFS and OS, it was found that the wild type of ERCCl codon 118C / C was 1.83 times as high as that of the heterozygote C / T (P0.016) and 1.8395% (1.12-2.99), and 1.94 times as high as the mutant of ERCCl codon 118T / T (P0.010% 1.9495CI1.17-3.27). Conclusion: compared with other genotypes, carrying ERCCl codon 118C/C genotypes has better objective chemotherapeutic response rate, and prolonging PFS and total OS.ERCCl codon 118C / C may be the key molecular markers for predicting the chemosensitivity of advanced bladder cancer.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.14

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