Involvement of C677T MTHFR variant but not A1298C in methotrexate-induced toxicity in acute lymphoblastic leukemia

Abstract

Background Methotrexate (MTX) is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5, 10 Methylenetetrahydrofolate to 5-methylene tetrahydrofolate by methylenetetrahydrofolate reductase (MTHFR). Variants of the Methylenetetrahydrofolate reductase (MTHFR) and MTX related toxicities were largely investigated in several populations, nevertheless, the results are conflicting. Objective This study aimed to assess the prevalence of MTHFR SNVs: C677>T and A1298>C in Tunisian patients with ALL and the relation to the frequency of drug-induced complications. Methods 28 ALL patients were included in the study. They were treated according to EORTOC, in which a high dose of MTX (HDMTX) was prescribed. A toxicity score (ST) is calculated for each patient, summing the grades of toxicities. Genotyping of MTHFR variants was done with a PCR-based restriction fragment length polymorphism assay. Results The toxicity’s score (TS) was higher with C677T variant compared to wild genotype (C677C) (TS = 4; IC95% [−2.65–13.32] versus TS = 2.5; IC95% [1.65–4.55], respectively; p = 0.2); but lower with the A1298C mutation compared to those with the wild genotype (A1298A) (TS = 2.5; IC95% [0.48–4.77], versus TS =3; IC95% [1.9–5.69], p = 0.4). HDMTX-related toxicity is associated with the 677CT genotype in ALL patients (RR = 1.41, p = 0.2); not for the A1298C [OR = 0.46, [0.08–2.61], p = 0.18]. Conclusion Our preliminary findings highlight the impact of the C677T variant of MTHFR, but not the A1289C; in HD-MTX chemotherapy-related adverse effects in younger Tunisian ALL.

Severe Adverse Toxic Effects of Low-Dose Methotrexate Treatment on an Ectopic Pregnancy Patient With Methylenetetrahydrofolate Reductase Mutations: A Case Report

“…Two of the most investigated polymorphisms within the MTHFR gene are single nucleotide polymorphisms (SNPs) at the mRNA positions 677 (rs1801133) and 1,298 (rs1801131) ( 8 ). However, these findings were mainly found in the patients with rheumatoid arthritis or the hematological malignancies ( 14 – 16 , 27 ). This is the first report on serious adverse toxic effects of LD-MTX on an EP patient with MTHFR mutations.…”

“…A number of previous studies have shown that severe adverse toxic effects of LD-MTX are associated with polymorphisms of methylenetetrahydrofolate reductase ( MTHFR ) gene, such as MTHFR 677TT and 1298AA ( 8 , 14 – 16 ), as the polymorphisms of MTHFR gene can decrease the MTX clearance, leading to the metabolite accumulation ( 15 , 17 ). For the patients who had serious adverse toxic effects of LD-MTX, it is essential to consider genetic abnormalities.…”

MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

“…6,7 To date, numerous studies have analyzed separately the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in ALL, but the conclusions remain controversial. [8][9][10][11] To the best of my knowledge, most of these studies do not analyze haplotypes.…”

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“…Two of the most investigated polymorphisms within the MTHFR gene are single nucleotide polymorphisms (SNPs) at the mRNA positions 677 (rs1801133) and 1,298 (rs1801131) (8). However, these findings were mainly found in the patients with rheumatoid arthritis or the hematological malignancies (14)(15)(16)27). This is the first report on serious adverse toxic effects of LD-MTX on an EP patient with MTHFR mutations.…”

“…A number of previous studies have shown that severe adverse toxic effects of LD-MTX are associated with polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene, such as MTHFR 677TT and 1298AA (8,(14)(15)(16), as the polymorphisms of MTHFR gene can decrease the MTX clearance, leading to the metabolite accumulation (15,17). For the patients who had serious adverse toxic effects of LD-MTX, it is essential to consider genetic abnormalities.…”