Kuramochi Hidekazu, Tanaka Koji, Oh Daniel, Lehman Bethany J, Dunst Christy M, Yang Dong Yun, De Meester Steven R, Hagen Jeffery A, Danenberg Kathleen D, De Meester Tom R, Danenberg Peter V
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
Int J Oncol. 2008 Jan;32(1):201-8.
Thymidylate synthase (TS) is known to have polymorphisms in the 5' and 3' untranslated region (UTR). These polymorphisms have been reported to be associated with high TS expression and chemoresistance to 5-FU. The aim of this study was to examine the prognostic roles of the 5'-UTR and 3'-UTR TS polymorphisms in esophageal adenocarcinoma patients, as well as their relation with TS mRNA expression. Eighty-three patients with esophageal adenocarcinoma were assessed. Thirty-four had received 5-FU containing chemotherapy and 49 were treated with surgery alone. Surgically resected tumor tissues were analyzed for TS genotype and TS mRNA expression using a quantitative real-time RT-PCR method. No survival difference was seen between the patients with 3RG allele (3RG group) and non-3RG group among surgery-alone patients. However, among patients with a history of 5-FU-based chemotherapy, the non-3RG group showed significantly better overall survival compared to the 3RG group (p=0.02). Moreover, whereas chemotherapy produced a significant increase in survival for the non-3RG group patients, those in the 3RG group obtained no survival benefit from chemotherapy. When patients were classified by low or high TS mRNA expression levels, low TS expressers obtained survival benefit from chemotherapy while high TS expressers did not, although there was no difference of median TS mRNA levels between 3RG and non-3RG group. The 3'-UTR polymorphism was not associated with overall survival. These results suggest that the status of the TS 5'-UTR polymorphism and TS mRNA expression are independent predictive markers for survival benefit from 5-FU-based therapy.
已知胸苷酸合成酶（TS）在5'和3'非翻译区（UTR）存在多态性。据报道，这些多态性与TS高表达以及对5-氟尿嘧啶（5-FU）的化疗耐药性有关。本研究的目的是探讨5'-UTR和3'-UTR TS多态性在食管腺癌患者中的预后作用，以及它们与TS mRNA表达的关系。对83例食管腺癌患者进行了评估。其中34例接受了含5-FU的化疗，49例仅接受手术治疗。使用定量实时RT-PCR方法对手术切除的肿瘤组织进行TS基因型和TS mRNA表达分析。在仅接受手术治疗的患者中，3RG等位基因患者（3RG组）和非3RG组之间未观察到生存差异。然而，在有5-FU化疗史的患者中，非3RG组的总生存期明显优于3RG组（p = 0.02）。此外，化疗使非3RG组患者的生存期显著延长，而3RG组患者未从化疗中获得生存益处。当根据TS mRNA表达水平低或高对患者进行分类时，低TS表达者从化疗中获得生存益处，而高TS表达者则没有，尽管3RG组和非3RG组之间的TS mRNA水平中位数没有差异。3'-UTR多态性与总生存期无关。这些结果表明，TS 5'-UTR多态性状态和TS mRNA表达是基于5-FU治疗生存获益的独立预测标志物。
