Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukaemia and chronic myelogenous leukaemia in the Korean population

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism, DNA methylation and synthesis. We investigated the association between MTHFR polymorphisms and the risks of acute and chronic leukaemias. MTHFR C677T and A1298C were genotyped in 396 Korean individuals using multiplex polymerase chain reaction/restriction fragment-length polymorphism. They were acute lymphoblastic leukaemia (ALL, n = 89), acute myeloid leukaemia (AML, n = 55), biphenotypic acute leukaemia (n = 12), chronic myelogenous leukaemia (CML, n = 40), and normal controls (n = 200). C677T genotypes were not associated with the risk of each disease. A1298C variants, however, significantly decreased the risks of ALL and CML compared with 1298AA. Odds ratios and 95% confidence intervals of 1298AC and 1298AC + CC were 0.53 (0.31-0.93) and 0.54 (0.31-0.93) in ALL, and 0.34 (0.14-0.80) and 0.40 (0.18-0.89) in CML, respectively, compared with 1298AA. These findings demonstrate that the development of ALL and CML is more dependent on folate status, and more susceptible to DNA instability than that of AML. In addition, A1298C rather than C677T may be a more important genetic risk modifier in leukaemogenesis at least in the Korean population.

Association between methylene tetrahydrofolate reductase and glutathione S-transferase M1 gene polymorphisms and chronic myeloid leukemia in a Brazilian population

“…Although this study did not assess folate or Hcy levels, neither the 1298CC nor the heterozygous state has been associated with higher plasma Hcy or lower plasma folate concentration, phenomena evident with homozygosity 677TT (van der Put et al, 1998). Moreover, a decreased CML risk in Asians (Hur et al, 2006) and fewer relapses after bone marrow transplant in Caucasians (Robien et al, 2004) have been observed for the 1298AC genotype.…”

“…Polymorphic variants of several genes, diet, environmental exposure to carcinogens and individual immune system's characteristics are potential factors that increase predisposition to leukemia (Bowen et al, 2003). Association studies have been performed to identify genetic variants associated with CML susceptibility, and among them are methylenetetrahydrofolate reductase (MTHFR) (Hur et al, 2006;Moon et al, 2007;Barbosa et al, 2008), glutathione S-transferases (GSTs) (Hishida et al, 2005;Souza et al, 2008), and haptoglobin (Hp) gene polymorphisms (Nevo and Tatarsky, 1986;Campregher et al, 2004).…”

“…However, under situations of decreased MTHFR activity, more MTHFR substrate is available for purine and pyrimidine synthesis, which may prevent imbalances of nucleotide pools during DNA synthesis and potentially oncogenic alterations in DNA methylation (Ma et al, 1997;Ulrich et al, 1999). Associations have been described between the common MTHFR polymorphisms C677T and A1298C and risk of leukemia (Skibola et al, 1999;Franco et al, 2001;Robien and Ulrich, 2003;Robien et al, 2004;Ismail et al, 2009), but few studies with CML have been published, with inconsistent results (Robien and Ulrich, 2003;Robien et al, 2004;Hur et al, 2006;Moon et al, 2007;Barbosa et al, 2008;Ismail et al, 2009). Therefore, studies in several ethnicities are required to better understand the biological significance of these polymorphisms in CML susceptibility, since they vary among ethnic groups (Franco et al, 1999;Robien and Ulrich, 2003).…”

Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan

“…Methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme, downstream of cSHMT, catalyzing the circulation of 5-methyltetrahydrofolate (5-CH 3 -THF) through the conversion of 5,10-CH 2 -THF, is required for homocysteine remethylation to methionine that is catalysed by methionine synthase (MS) and is served as the intersection for one-methyl group donor [13][14][15]. The genetic polymorphism of MTHFR gene has been identified at nucleotide 677 C [ T and 1298 A [ C, which encodes variants with amino acid substitutions of alanine to valine at position 225 and glutamate to alanine at position 432, respectively.…”

MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine

“…[9][10][11] Population-based studies have shown an association between genetic polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair and solid and hematological diseases. [12][13][14][15][16][17][18][19][20][21] Some of these studies also showed an association between specific polymorphisms and decreased of survival after chemotherapy. 8 As an example, Kim et al 5 reported that (1) MTHFR 677TT genotype is associated with a significantly increased risk for adult acute lymphoblastic leukemia, (2) TS polymorphisms are involved in the etiopathogenesis of AML and (3) both DNA synthesis and methylation play important roles in the pathogenesis of AML and MDS.…”