The complex interplay between folate metabolism and risk of acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) affects all agegroups, although it is much more common inpediatric patients, with a peak incidence betweenthe ages of 1 and 4 years and a median age of 13 yearsat diagnosis (Surveillance, Epidemiology and EndResults [SEER] 2003–2007 data). While deregula-tion of pathways that control cell proliferation,differentiation, and survival contributes to its patho-genesis, the precise etiology of ALL is not yetunderstood. Many patients with ALL are in factchildren, and few have predisposing genetic syn-dromes or known carcinogenic exposures, such asionizing radiation or chemotherapeutic agents.Therefore increasing attention is being placed onidentifying underlying factors that increase thesusceptibility to the development of ALL. Folatemetabolism is essential to numerous cellular pro-cesses, including DNA and RNA synthesis as well asmethylation reactions involving homocysteine andDNA [1,2]. Rapidly dividing cells, therefore, havehigh folate requirements, and polymorphisms infolate-related genes can alter the amount or distribu-tion of this substrate available to cells. This has ledinvestigators to examine possible associations be-tween polymorphisms in the wide variety of genesinvolved in folate metabolism and the developmentof ALL. While there is a growing body of literatureexamining such associations, the results are not allconcordant.In this issue of Leukemia and Lymphoma,Yang et al. record the results of their study evaluatingsuch associations in the Han Chinese population [3].This study reports on polymorphisms in ninedifferent folate-related genes in both adult andpediatric patients with ALL and found that in thepopulation studied, variations in RFC1 (reducedfolate carrier 1) and MTRR (methionine synthasereductase) confer an increased risk for developingadult ALL while MTHFR (methylenetetrahydrofo-late reductase) and ABCG2 (ATP-binding cassettesub-family G member 2) polymorphisms confer adecreased risk. No significant associations werefound between polymorphisms in any of the genesstudied and the risk of pediatric ALL.The most studied folate-related gene variants todate, in relation to ALL risk, are the 677C4T and1298A4C polymorphisms in MTHFR. While thereare conflicting results from various studies, severalmeta-analyses suggest a reduced risk of adult ALLwith the homozygous TT genotype but perhaps lessof a risk reduction with this genotype in pediatricpopulations [1,4,5], similar to what was observed byYang et al. in their report here [3]. There have beenseveral studies in pediatric populations, however,which identified a reduced risk of pediatric ALL withthe 677T allele [2,6]. Fewer studies are available onother genes involved in folate metabolism, and theresults in different populations vary. In general,though, studies that evaluated polymorphisms inRFC1 found a significantly increased relative risk ofALL in patients with the 80G4A variant [2,7],similar to the results reported by Yang et al. [3]. On