The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer

Abstract

Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

“…The effect of MTHFR polymorphisms in mediating this risk again show mixed results, being confirmed by multiple high level studies [26,[67][68][69], yet having no association found in other studies [97]. Multiple SNPs in SLCO1B1, an MTX transporter gene; efflux transporter genes ABCB1, ABCC4; as well as genes otherwise involved in folate metabolism such as GSTM1 and GSTT1 have been variably linked with MTX plasma levels, hepatotoxicity, and the occurrence of mucositis [30, 46, 56-61, 98, 99].…”

Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high‐dose methotrexate

“…Notwithstanding the clinical consequences, it is not yet possible to predict the characteristics of patients at risk for developing MTX toxicity because responses to MTX exhibit wide interpatient variability . Several pharmacogenetic studies have attempted to explain the observed interindividual variability, and a 677C>T single nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase gene ( MTHFR ), which encodes an enzyme involved in MTX metabolism, was studied most extensively …”

“…MTHFR plays a key role in the metabolism and homeostasis of intracellular folate, and the C>T substitution in MTHFR is reported to correlate with decreased MTHFR enzyme activity, thus contributing to a low folate level . Although the genetic association of MTHFR 677C>T with MTX toxicity was evaluated in several studies, the results were conflicting …”

“…The substantial heterogeneity of the studied populations was suggested as a possible explanation for the contradicting results because ethnicity, MTX doses, coadministered chemotherapeutic agents, and folinate rescue dosage regimens could alter the MTX toxicity profile . Most, if not all, previous studies allowed the inclusion of patients treated with an MTX‐based combination regimen or different MTX‐based chemotherapy protocols.…”

Pharmacogenetics of methotrexate in pediatric hematological neoplasm treatment: does it need a personalized regimen based on MTHFR polymorphisms?

“…Hagleitner et al studied in a Dutch cohort of 98 pediatric patients treated with high doses of MTX, the influence of MTHFR 677C> T on hepatotoxicity using a generalized estimating equation (GEE) analysis that showed an increased risk of developing hepatotoxicity for T allele versus C allele in patients with osteosarcoma (odds ratio: 1.8; 95% CI: 1.0-3.2; p = 0.04). However, this finding was not supported by a metaanalysis performing on seven studies and 1044 patients [6]. Also, in 2013, D'Angelo et al investigated in 95 pediatric patients affected by non-Hodgkin lymphoma (NHL) and treated with AIEOP LNH 97 and EURO LB-02 protocols, the role of C677T and A1298C MTHFR genetic polymorphisms in the risk of MTX-induced toxicities.…”