Influence of methylenetetrahydrofolate reductase gene polymorphisms on the outcome of pediatric patients with non-Hodgkin lymphoma treated with high-dose methotrexate

Abstract

High-dose methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent non-Hodgkin lymphoma (NHL). Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolizing genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene on the clinical toxicity and efficacy of MTX in pediatric patients with NHL (n = 95) treated with therapeutic protocols Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately six-fold greater risk of developing hematological toxicity compared with wild-type carriers, especially in the 1 g/m(2) treatment group (p = 0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype: T carriers had reduced disease-free survival compared with wild-type patients (67% vs. 100%). Our data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX in the 1 g/m(2) treatment group.

Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: Evidence from a meta-analysis

“…Of them, 14 articles were excluded after title and abstract assessment, while 31 articles met the crude inclusion criteria and were further evaluated. Among these remaining 31 publications, we further excluded two studies1526 that were covered by other included investigations2024, three case-only designed studies404142, and one more study in which genotype frequency data in the controls for both of the C677T and A1298C polymorphisms were deviated from HWE ( P = 0.009 for C677T and P = 0.040 for A1298C)38. Overall, 25 articles were included in the final meta-analysis.…”

Effect of folate status and methylenetetrahydrofolate reductase genotypes on the complications and outcome of high dose methotrexate chemotherapy in north Indian children with acute lymphoblastic leukemia

“…In stark contrast to the lack of studies on folate deficiency and toxicity of HD-Mtx, there have been a good number of studies in the literature which examined the association of MTHFR genotype with the complications of HD-Mtx. [ 8 9 10 11 12 ] Though this issue was investigated by various authors no consensus could be reached, and results have been mutually contradictory. The differences may have cropped in due to various reasons like sample size issues, non-uniform chemotherapy protocols including the dosage of Mtx and leucovorin.…”

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

“…51,52 Nine studies found the C677T mutation in MTHFR contributed to myelotoxicity. [53][54][55][56][57][58][59][60] The A1298C SNP was also associated with myelotoxicity in three studies 53,54,57 although two studies found this polymorphism to be protective. 61,62 Only a single study associated the G80A SNP with myelotoxicity.…”