Altered Folate Metabolism Maybeo the Develop Linked tment of Acute Lymphoblastic Leukemia in African American Children.

Acute lymphoblastic leukaemia (ALL) is the most common form of childhood cancer in the United States. The incidence of ALL is approximately 2-3-fold higher in Caucasian compared to African American (AA) children, suggesting potential differences in genetic susceptibility and/or exogenous exposures. Multiple epidemiologic studies have examined both genetic and environmental factors linked to the development of childhood ALL, primarily in Caucasian populations. Hence, identifying factors associated with racial differences in incidence of leukemia may provide new insights into the role of endogenous versus exogenous factors in the development of leukemia. A number of studies have reported relationships between folate metabolism and the risk of developing ALL including: i)maternal folate supplementation during pregnancy (reduced risk of ALL in offspring); and ii)polymorphisms of genes encoding enzymes involved in folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR) (increased and decreased risks). To date, no studies have been performed specifically examining the role of folate metabolism in AA children. The objective of this study was to identify factors associated with folate metabolism which may be linked to the development of ALL in AA children compared to healthy controls.

AA children with B-precursor (BP) ALL were enrolled from the Hematology/Oncology Division of Children's Hospital of Michigan, while healthy AA children were enrolled as controls. Patients' racial backgrounds were based on parental reporting. The frequencies of polymorphisms in the MTHFR [677C>T, 1298A>C], thymidylate synthase [TS 2R3R], cystathionine-β-synthase [CBS 844ins(68)], and reduced folate carrier [RFC 80G>A] genes were determined by genotyping between AA childhood BP-ALL [n=26; 14 males] and healthy AA children [n=87; 47 males]. The distributions of genotypes between cases and controls were compared using Fisher's exact test.

The genotype distributions of the polymorphisms of the folate pathway genes are summarized in Table 1. The frequencies of the MTHFR gene variants 677 CT/TT were 2-fold higher in the ALL cohort than that in the healthy control cohort. MTHFR 677 CT/TT was significantly associated with a risk of developing ALL in the AA patients. There were no significant differences in the distributions of the TS, CBS, or RFC polymorphisms between the groups. High birth weight has been associated with an increased risk of developing ALL, though we found no significant difference in birth weights between ALL and control groups.

Our study is the first to demonstrate that there is a higher frequency of the variant MTHFR C677T polymorphism (associated with reduced enzyme activity and altered distribution of folate forms) in AA children with ALL compared to healthy controls. Low MTHFR enzyme activity leads to imbalances in the thymidylate and de novo purine biosynthetic pathways, ultimately affecting DNA synthesis and repair and likely increasing the risk of leukemia. Thus, the role of altered folate metabolism may contribute to the development of ALL in AA children similar to Caucasian children, although additional studies are still required to identify factors linked to the higher incidence of ALL in Caucasian children and/or low incidence in AA children.

No relevant conflicts of interest to declare.