We evaluated DNA polymorphisms in the thymidylate synthase (TS) and 5,10-methylene-tetrahydrofolate reductase (MTHFR) genes for an association with response and survival in locally advanced gastric cancer treated with 5-FU based preoperative chemotherapy (CTx). DNA of 238 patients (CTx-group: total n 5 135, completely resected (R0) n 5 102; without CTx: R0 n 5 103) was isolated from blood or from nontumorous tissues. In the CTx-group, genotyping of the tandem repeat and the G/C polymorphism in the triple repeat in the promoter region of the TS gene and of the C677T polymorphism of the MTHFR gene was performed. None of the TS or MTHFR genotypes were associated with histopathological response and only the TS tandem repeat polymorphism was significantly related to survival (all patients n 5 135, p 5 0.002; R0 resected patients n 5 102, p 5 0.007; log-rank test). Multivariate analysis revealed ypN (p < 0.001) and the TS tandem repeat polymorphism as independent prognostic factors in the CTx-R0-group (p 5 0.003). Analyzing the prognostic significance of the TS polymorphisms in the R0-group without CTx, TS genotypes were not significantly associated with survival. Comparing survival between R0 patients with and without CTx in the respective TS genotype groups of the tandem repeat polymorphism, a significant survival benefit for the patients with CTx was found for the 2rpt/2rpt (n 5 49; p 5 0.002) and 2rpt/3rpt genotypes (n 5 99; p 5 0.004), but not for the 3rpt/3rpt genotype (n 5 57; p 5 0.93). Patients' survival after CTx was associated with the TS tandem repeat polymorphism. CTx did not improve survival of patients with the 3rpt/ 3rpt genotype. Thus, a different therapy might be more appropriate for these patients. ' 2006 Wiley-Liss, Inc.Key words: thymidylate synthase; MTHFR; DNA polymorphism; preoperative chemotherapy; 5-fluorouracil; cisplatin; gastric carcinoma Neoadjuvant chemotherapy for advanced gastric cancer has been used in several clinical trials. However, only 30-40% of patients respond and the majority undergoes several months of toxic, expensive therapy without a survival benefit.1-3 Response to chemotherapy is considered to be highly complex and may be influenced by specific genetic alterations in the tumors as well as by inherited interindividual variability in genes involved in drug metabolism. Presently, there is no reliable assay that can be used to predict chemotherapy response in gastric carcinoma in clinical practice. Thus, the identification of molecular genetic parameters that are associated with response and prognosis is of utmost interest.Most chemotherapeutic regimens used in the neoadjuvant treatment of advanced gastric carcinoma contain 5-FU. 5-FU is an inhibitor of thymidylate synthase (TS), a key enzyme in nucleotide metabolism. The promoter enhancer region of the TS gene contains polymorphic 28 base pair tandems repeats, and the presence of the triple repeat (3rpt) has been shown to be associated with a 2-4 fold increase in protein expression in comparison to the double repeat (2rpt)...
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