Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies

Abstract

Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin's lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies.

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

“…Hepatotoxicity was analyzed in 7 studies, only Fukushima et al28 showed significant results in their cohort of children, which as previously mentioned, mixed 82 ALL patients and 21 NHL patients. In this study, 1298CC genotype patients presented a lower hepatic toxicity risk comparing to the 1298AA genotype patients.…”

“…From them, only 5 found significant associations with toxicity, but with contradictory results: 2 studies related the T variant allele to a decrease in toxicity risk,24,25 whereas the other 3 associated it to increased risk (Table 1). 26–28…”

“…Hepatotoxicity was analyzed in 7 studies, and only the study of Fukushima et al28 found significant association for 677CT/TT carriers. This study was conducted in a cohort of 103 Japanese patients, that mixed ALL (n=82) and non-Hodgkin lymphoma (NHL) (N=21) patients.…”

“…From them, only 3 studies found significant association. Moulik et al31 and Haase et al25 showed the C variant allele favoring an increase in toxicity, whereas Fukushima et al28 showed a protective role for the C variant allele. When the different toxicities were considered, almost all the results found no significant associations (Table 4).…”

“…From them, 2 studies showed significant results but with opposite effect. Fukushima et al28 demonstrated that individuals with AC-CC genotypes presented increased Event Free Survival (EFS) (versus AA genotype), whereas Radtke et al’s39 study found that individuals with AC or CC genotypes showed decreased EFS (versus AA genotype) (Table 6). The other 4 studies showed no association between A1298C and outcome, which is in line with the previously published meta-analysis of He et al35 and other 3 studies.…”