Objective: To study the association between Thymidine Phosphorylase (TYMP) genetic variation and clinical outcomes and safety of postoperative colorectal cancer (CRC) patients. Methods: A total of 235 patients with colorectal cancer underwent surgical treatment were included in this retrospective analysis. Peripheral blood and the postoperative tissue specimen of the CRC patients were collected for the genotyping of polymorphism and TYMP mRNA expression, respectively. The correlation between polymorphism and clinical outcomes and safety of postoperative CRC patients were analysed. Results: Located in the upstream, 5633C>T was of clinical significance. The prevalence of 5633C>T in TYMP among the CRC patients were as follows: CC genotype 149 cases (63.40%), CT genotype 73 cases (31.06%), TT genotype 13 cases (5.54%), minor allele frequency of 5633C>T is 0.21. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.313). CT genotype and TT genotype patients were merged in the comparison of prognosis. The survival analysis of patients with different genotypes found that the median Overall Survival (OS) of CT/TT genotype and CC genotype were 5.8 and 4.5 year, which was statistically significant (P=0.009). Adjusted in multivariate Cox regression analysis, CT/TT genotype was an independent favorable factor for OS (HR=0.67, P=0.015). Additionally, of the 87 postoperative tissue specimens, the results showed that the expression of TYMP in cancer tissues of the patients with CT or TT genotypes were significantly higher than those of the wild type CC genotype patients (P=0.019). And the safety analysis showed that the incidence of grade 3 hand-foot syndrome among CT/TT genotype patients were higher than that of CC genotype patients (33.72% vs 20.13%, OR=1.68, P=0.021). Conclusion: The polymorphism 5633C>T of TYMP may impact the prognosis of CRC patients received adjuvant chemotherapy by influencing the mRNA expression of TYMP.
目的： 探讨胸苷磷酸化酶(TYMP)的基因遗传变异对R0切除术后结直肠癌(CRC)患者接受辅助化疗疗效及安全性的影响。 方法： 本研究为回顾性分析，纳入235例术后接受辅助化疗的CRC患者。收集患者外周血及术后癌组织标本分别用来进行TYMP多态性位点基因分型及TYMP基因表达测定，并对纳入研究患者的疗效和安全性进行相关性分析。 结果： 位于上游区域的5633C>T位点和预后有关联。TYMP基因的5633C>T位点在CRC患者中的突变频率为：CC型149例(63.40%)，CT型73例(31.06%)，TT型13例(5.54%)，最小等位基因频率为0.21，三种基因型分布频率符合哈迪温伯格平衡(P＝0.313)。单变量的生存分析结果显示：携带突变基因的CT/TT型患者和野生型CC型患者的中位总生存期(OS)分别为5.8和4.5年，差异有统计学意义(P＝0.009)。经过多变量的Cox模型校正之后发现CT/TT基因型患者较好的预后影响意义依然存在(HR＝0.67, P＝0.015)。另外，进一步在87例癌组织标本的mRNA表达分析中发现，突变的CT或TT型患者相对于野生型的CC型患者，癌组织中TYMP的mRNA表达明显较高，差异有统计学意义(P＝0.019)。安全性分析结果表明5633C>T位点CT/TT型患者3级手足综合征的发生率高于野生型CC型的患者(33.72%比20.13%, OR＝1.68, P＝0.021)。 结论： TYMP基因5633C>T位点可能通过影响TYMP基因mRNA的表达从而影响接受辅助化疗的CRC患者的预后。.
Keywords: Colorectal cancer; Single nucleotide polymorphism; Thymidine phosphorylase; Treatment outcome.