Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis.

Lei Zhong,Min Chen,Shao-Min Zhu,Qian Peng,Jun-Lan Chuan,Xia He,Yuan Zhang

doi:10.18632/oncotarget.24933

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of MTHFR polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were applied to assess the strength of association. A total of 2118 colorectal cancer patients from 21 studies were included in the meta-analysis. Overall, there was no significant association between MTHFR C677T (rs1801133) or A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (allele model, dominant model, and recessive model) and stratification analysis, except for the retrospective study subgroup in the dominant model of MTHFR C677T and the “5-Fu + FA” treatment group in the allele contrast of MTHFR A1298C. No or moderate heterogeneity was observed in all genetic models. This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the clinical response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

Highlights

Fluoropyrimidines, such as 5-fluorouracil (5-FU), and the oral prodrugs capecitabine and tegafur have been widely used in the treatment of a variety of solid cancers for a long time, especially colorectal cancer (CRC) [1,2,3]
According to the inclusion/exclusion criteria, data from 21 studies that investigated the association between Methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C polymorphisms and response to fluoropyrimidine-based chemotherapy in CRC patients were collected for the meta-analysis [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]
21 studies including 2118 patients reported tumor response events associated with MTHFR C677T polymorphism, and 13 studies provided 1496 patients for testing the association of MTHFR A1298C variant with response to chemotherapy (Table 1)

Summary

Introduction

Fluoropyrimidines, such as 5-fluorouracil (5-FU), and the oral prodrugs capecitabine and tegafur have been widely used in the treatment of a variety of solid cancers for a long time, especially colorectal cancer (CRC) [1,2,3]. Fluoropyrimidine drugs themselves have no anti-tumor activity, but they can be metabolized into fluorodeoxyuridine monophosphate (FdUMP). 5, 10-methylenetetrahydrofolate (5, 10-MTHF) and thymidylate synthase (TS), thereby inhibiting the activity of TS. This prevents the conversion of 2′-deoxyuridine5′-monophosphate into 2′- deoxythymidine-5′-mono phosphate, the latter of which is an essential precursor for DNA synthesis [4]. Methylenetetrahydrofolate reductase (MTHFR), www.oncotarget.com the most critical enzyme in folate-metabolizing pathway, catalyzes the irreversible conversion of 5, 10- methylenetetrahydrofolate (5, 10-MTHF) to 5-methyltetrahydrofolate, and reduces the amount of 5, 10-MTHF available for binding to FdUMP and TS [5]. The activity of MTHFR may be an important factor for predicting the clinical response to fluoropyrimidine-based chemotherapy. MTHFR C677T and A1298C polymorphisms are potential predictors for the clinical response to fluoropyrimidine-based chemotherapy

Methods

Results

Conclusion