Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy?

Abstract

Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) may play a central role in the action of 5-FU, an inhibitor of thymidylate synthase, by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The aim of this study was to ascertain whether two polymorphisms in the MTHFR gene (677C>T and 1298 A>C) could be used as genomic predictors of clinical response to fluoropyrimidine-based chemotherapy (in combination with irinotecan or oxaliplatin). Ninety-four patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-containing chemotherapy as a first line treatment were studied. The results suggest that the MTHFR genotype cannot be considered as an independent factor of outcome in colorectal cancer patients under 5-FU-based chemotherapy.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

“…So far, clinical studies including variants in TS 30-34 and MTHFR [35][36][37] have not shown univocal results. It is to be said that findings across clinical studies with TS and MTHFR polymorphisms in CRC patients are poorly comparable.…”

The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer

“…First, indeed, from a simple blood sample taken before chemotherapy, physicians can be warned of a high risk of severe or even lifethreatening toxicity for a patient, that is relevant DPD and/or MTHFR variants regardless of the 5-FU regimens and the type of cancer. 23,29 Taking into account the wide use of 5-FU and other fluoropyrimidines, this is of major interest. In practice, in cases of a DPD deficiency, either 5-FU dose management based on a pharmacokinetic follow-up can be proposed after a reduced first dose of 5-FU or the switch to another drug, such as raltitrexed.…”

“…This concept was clearly demonstrated both in experimental studies and in clinical settings. [18][19][20][21][22][23] The purpose of this study was to analyze the correlation between TS, DPD and MTHFR germinal polymorphisms on efficacy and toxicity of fluorouracil and leucovorin chemotherapy in patients with advanced CRC. Our objective was to provide a tool for physicians to determine before treatment patients at risk of 5-FU toxicity or resistance.…”

“…[20][21][22][23] For each polymorphism, a prior biotinyled PCR with specific primers (Table 7) was performed. Briefly, DNA simple strands were obtained by the purification of the biotinyled PCR products with Sepharose balls coupled to streptavidine and after denaturation with washing in different baths (ethanol 70%, then NaOH 0.2 M and finally washing buffer pH 7.6 which washed away unbiotinyled products).…”

Pharmacogenetics and biomarkers in colorectal cancer

“…Even though the mutations do not bear prognostic value on their own, it has been suggested that the combination of wild-type MTHFR genotype (1298A or 677C) with the 3R/3R TS genotype shows significantly lower overall survival. 63 The clinical importance of the MMR status of tumors with regard to prognosis and response to adjuvant 5-FU chemotherapy has been increasingly studied the last few years. Patients diagnosed with stage II colorectal cancer, whose tumors were found to have unstable microsatellites (MMR deficient or MSI þ ), carry a better prognosis than do the microsatellite stable (MMR proficient or MSIÀ) ones.…”