The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

Abstract

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy7surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P ¼ 0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P ¼ 0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value.

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

“…This may be attributable to the fact that the majority of tumour samples were retrieved from the original diagnostic block (Johnston et al, 2003). The lack of correlation between genotype and outcome in this study is similar to recent data from Sarbia et al (2006), who demonstrated that the MTHFR C677T and TS tandem repeat polymorphism had no predictive value in patients with oesophageal squamous cell carcinoma undergoing multimodality treatment.…”

Evaluating the drug-target relationship between thymidylate synthase expression and tumor response to 5-fluorouracil: Is it time to move forward?

“…In their study, determination of TS tandem repeat provided no value in predicting the outcome of patients with locally advanced squamous cell esophageal cancer after treatment with 5-FU based chemotherapy. 58 These data are supported by the study from Nief et al in which 60 human cancer cell lines from the NCI were evaluated for three relevant TS gene polymorphisms, and no relationship was found between 5-FU cytotoxicity and TS expression or polymorphisms. 77 However, there are studies that contradict these findings and suggest that TS polymporphism status may be a useful predictor of 5-FU response.…”

Folate intake, Methylenetetrahydrofolate Reductase Polymorphisms in Association with the Prognosis of Esophageal Squamous Cell Carcinoma

“…In additional, the activity of MTHFR, folate metabolic enzyme, is also involved in the folate metabolic and DNA methylation process. As a key enzyme in folate metabolism, the product of MTHFR serves as the carbon donor for the methylation of homocysteine tomethionine, which is catalyzed by the enzyme MTR (Sarbia et al, 2006). Therefore, the MTHFR C677T may play a role in the prognosis of esophageal cancer.…”