Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia

Abstract

BackgroundThere is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association.ProcedureWe obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes.ResultsTwenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 109/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46–16.31); non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions.DiscussionMaternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL.

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

“…The present finding of a correlation between the MTR 2756A > G polymorphism and DNMT1 promoter methylation levels in blood DNA not only strengthens the contribution of this genetic variant to the DNA methylation levels in leukocytes, but it could also be of relevance for those disorders, such as hematological malignancies, autoimmune/inflammatory disorders, and solid tumors, that are linked to impaired DNMT1 methylation and/or expression [5][6][7][8][9][10][11][12]. For example, changes in DNMT1 methylation levels were observed in peripheral blood DNA samples from ALL patients [8], the MTR 2756A > G polymorphism was linked to the risk of pediatric ALL [34], and several maternal polymorphisms of the MTR gene were recently proposed as responsible of aberrant methylation of ALL-related genes in their offspring [35]. Furthermore, the MTR 2756A > G polymorphism was also linked to the risk of autoimmune/inflammatory diseases and solid tumors, all characterized by impaired DNMT activities and global and gene-specific DNA methylation changes [36][37][38][39], suggesting that the investigation of the contribution of this polymorphism to DNMT1 methylation levels is warranted in all these disorders.…”