Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients

Abstract

Methylenetetrahydrofolate reductase (MTHFR) controls intracellular CH2FH4 concentrations (required for optimal fluoropyrimidine efficacy) by irreversibly converting CH2FH4 into 5-methyltetrahydrofolate. MTHFR 677C>T and 1298A>C polymorphisms are linked to altered enzyme activity. Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours. MTHFR polymorphisms in position 677 and 1298 were analysed in 98 colorectal cancer patients with unresectable liver metastases (57 men, 41 women, mean age 64 years) receiving 5FU-folinic acid. 677C>T and 1298A>C genotypes were determined simultaneously by melting curve analyses on liver metastases. 677C>T genotype distribution was 46.9% wt/wt, 34.7% wt/mut and 18.4% mut/mut; that of 1298A>C was 52.0% wt/wt, 35.7% wt/mut and 12.3% mut/mut. The response rate was not related to 1298A>C genotype but was significantly linked to 677C>T genotype (response rate: 40%, 21% and 56% in wt/wt, wt/mut and mut/mut, respectively; P = 0.040), with an increased response rate in mut/mut tumours relative to wt/wt (odds ratio = 1.88). Thymidylate synthase activity measured in metastases was a significant predictor of 5FU responsiveness and the addition of the 677C>T genotype improved model prediction. MTHFR 1298A>C polymorphism was significantly linked to specific survival, with homozygous mutated patients having the worst prognosis (P = 0.009, relative risk = 2.48 in mut/mut versus wt/wt). MTHFR 1298A>C genotype remained a significant predictor in a multivariate analysis including metastasis characteristics. The results suggest that MTHFR genotypes are relevant and independent factors of patient outcome in 5FU-based treatment of advanced colorectal cancer.

DNA methylation and sensitivity to antimetabolites in cancer cell lines

“…Etienne et al also showed that SNPs at MTHFR-A1298C were unrelated to the outcome of 5-FU-based chemotherapy in the clinical setting, but were significantly linked to survival, with homozygous mutated (CC) patients having the worst prognosis (12). This also supported previous findings (23).…”

“…Predicting the direction of the metabolic pathway of reductive folates, whether for DNA synthesis or methylation, is crucial for determining the susceptibility of cancers to antimetabolites such as 5-FU. Two single nucleotide polymorphisms (SNPs) of MTHFR, C677T and A1298C, alter the activity of the methylenetetrahydrofolate reductase enzyme, and have been intensively evaluated for their association with 5-FU efficacy (11)(12)(13). However, there are many discrepancies between the results.…”

Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer

“…Some studies have reported that the MTHFR 677T mutation, linked to the reduced activity of MTHFR, increases chemosensitivity to 5-FU (Cohen et al, 2003;Sohn et al, 2004), whereas others have had inconsistent results (Etienne et al, 2004;Ruzzo et al, 2006). Although MTHFR and DHFR are key enzymes in folate metabolism, the role of MTHFR gene expression in the antitumour activity of 5-FU remains controversial.…”

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…46 In a recent study of 98 dissiminated colorectal cancer patients, the C677T mutation was also associated with higher response rates on 5-FU/folinic acid chemotherapy. 47 In the same study, the A1298C polymorphism was studied, but this was not related to the response rate. The exact roles of the MTHFR polymorphisms have to be elucidated in larger prospective clinical trials.…”