摘要目的 探讨胸苷磷酸化酶(TYMP)的基因遗传变异对卡培他滨方案在胃癌辅助化疗疗效的影响.方法 回顾性分析2011年1月至2017年6月在郑州大学人民医院普外科住院诊治的术后接受卡培他滨为基础辅助化疗的198例胃癌患者的临床资料.收集患者外周血及术后癌组织标本分别进行TYMP多态性位点基因分型及TYMP基因mRNA表达测定,并对纳入研究患者TYMP多态性位点的基因型和疗效及安全性进行相关性分析.结果 位于上游区域的rs11479位点和预后相关,该位点在研究人群中的分布频率为:CC型125例(63.13％),CT型65例(32.83％),TT型8例(4.04％),最小等位基因频率为0.20,该位点基因型分布频率符合哈迪温伯格平衡(P=0.901).对不同基因型患者进行疗效分析发现:CT/TT和CC基因型患者的3年无病生存率别为73.97％和65.60％,差异有统计学意义(P =0.003).CT/TT和CC基因型患者的3年总生存率分别为83.56％和72.80％,差异有统计学意义(P=0.012).对无病生存期构建多变量的Cox模型校正之后CT/TT基因型对无病生存期的影响差异有统计学意义(OR=0.55,P=0.011).安全性分析结果并未发现该位点和2级以上不良反应的相关性.进一步在79例术后癌组织标本的mRNA表达分析中发现,rs11479位点CT/TT基因型患者相对于野生型的CC患者,癌组织标本中TYMP的mRNA表达显著较高,差异有统计学意义(P＜0.001).结论 TYMP基因rs11479位点可能通过影响TYMP基因mRNA的表达进而影响接受卡培他滨为基础辅助化疗的胃癌患者的疗效.

abstractsObjective To investigate the association between Thymidine phosphorylase (TYMP) genetic variation and clinical outcomes of postoperative gastric cancer (GC) patients received capecitabine based regimens.Methods A total of 198 GC patients underwent surgical treatment and received capecitabine based adjuvant chemotherapy were included in this retrospective study.Peripheral blood and the postoperative tissue specimen of the GC patients were collected for the genotyping of polymorphism and TYMP mRNA expression,respectively.The correlation between polymorphism and clinical outcomes and safety of postoperative GC patients were analysed.Results Located in the upstream,rs11479 was of clinical significance.The prevalence of rs11479 in TYMP among the GC patients were as follows:CC genotype 125 cases (63.13％),CT genotype 65 cases (32.83％),TT genotype 8 cases (4.04％),minor allele frequency of rs11479 is 0.20.The distribution of three genotypes were in accordance with Hardy-Weinberg Equilibrium (P =0.901).The analysis results of patients with different genotypes found that the 3-year disease free survival rate of the patients with CT/TT genotype and CC genotype were 73.97％ and 65.60％,respectively,which was statistically significant (P =0.003).In terms of overall survival,the 3-year overall survival rate of the two genotypes were 83.56％ and 72.80％ (P =0.012),respectively.Adjusted in multivariate Cox regression analysis,CT/TT genotype was an independent favorable factor for disease free survival (OR =0.55,P =0.011).Safety analysis indicated that there was no significant association between genotypes and grade 2 adverse reaction.Additionally,of the 79 postoperative tissue specimens,the results showed that the expression of TYMP in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the wild type CC genotype patients (P ＜ 0.001).Conclusion The polymorphism rs11479 of TYMP have favorable influence on the clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy treatment through changing the mRNA expression of TYMP.