The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children

Abstract

The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

“…Supplement of folic acid was demonstrated to resolve the attacks of migraine [30]. These were in accordance with the mechanisms of MTHFR in ALL [11–13], indirectly illustrating the creditability that rs4846049 polymorphism (G allele or GG genotype) led to reduced expression of MTHFR and promoted the development of ALL as reported in our study.…”

“…Recently, two nonsynonymous single nucleotide polymorphisms (SNPs) in the MTHFR gene have been revealed to be associated with decreased enzyme activity, including C677T (rs1801133, alanine-to-valine substitution at codon 222 within the N -terminal catalytic domain of exon 4) and A1298C (rs1801131, glutamate-alanine substitution at codon 429 within SAM regulatory domain of exon 7) [9, 10]. Therefore, 677T (or CT, TT genotype) or 1298C (or CC, CA genotype) allele may be a risk factor for the development of ALL, which has been demonstrated in several studies [11–13]. However, conflicting conclusions were also reported by other scholars.…”

Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: Evidence from an updated meta-analysis

“…Totally 66 studies were included in the present meta-analysis regarding the relationship between C677T polymorphism of MTHFR gene and ALL. 1,5,9–68…”

Association between A1298C and C677T methylenetetrahydrofolate reductase gene polymorphisms and the risk of acute lymphoid and myeloid leukemia

“…Several polymorphisms of MTHFR enzyme have been identified from which the C677T and A1298C are the most important ones. C677T occurs in exon 4 and results in an alanine to valin change at codon 222 while the second common polymorphism A1298C, is transversion of A to C at position 1298, results in glutamate to alanine in codon 7 [15,16]. These polymorphisms decrease the enzyme activity and change distribution of intracellular folate metabolites that cause accumulation of 5-10 MTHFR, the precursor for synthesis of purine and thymidylate [16,17].…”