TY - JOUR
T1 - Maternal Red Blood Cell Folate and Infant Vitamin B 12 Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia
AU - Potter, Catherine
AU - Moorman, Anthony Vincent
AU - Relton, Caroline Laura
AU - Ford, Dianne
AU - Mathers, John Cummings
AU - Strathdee, Gordon
AU - McKay, Jill Ann
N1 - Funding Information:
J.A.M. designed the study and drafted the manuscript. J.A.M. compiled and determined the altered methylation in ALL gene list from the literature, carried out laboratory analysis (with the exception of pyrosequenc-ing analysis of the ASCL2 gene), and statistical analysis. C.H. carried out data analysis and interpretation. G.S. contributed to study design. A.V.M. and C.R. provided samples for analysis. D.F. and J.C.M. give permission to access and utilize genome-wide methylation data from mouse model of folate depletion. All authors contributed to revisions of, and approved, the final manuscript. This work was supported by the Newcastle upon Tyne Hospitals Special Trustees NHS Foundation Trust under Grant BH112012; North of England Children’s Cancer Research Fund (NECCR) (salary support (J.A.M.)) under Core Grant Funding. No funding bodies were involved in the design of the study, collection, analysis, interpretation of data, or in writing the manuscript. The authors acknowledge the contribution of Masters student, Nurul Aqilah Ali, who carried out pyrosequencing analysis for the ASCL2 gene.
PY - 2018/11
Y1 - 2018/11
N2 - Scope: Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated. Methods and Results: Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate-responsive genes (n = 526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n = 148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p = 0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p = 0.016). Conclusion: Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.
AB - Scope: Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated. Methods and Results: Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate-responsive genes (n = 526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n = 148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p = 0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p = 0.016). Conclusion: Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.
KW - DNA methylation
KW - acute lymphoblastic leukemia
KW - biomarkers
KW - folic acid
KW - maternal
KW - vitamin B
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U2 - 10.1002/mnfr.201800411
DO - 10.1002/mnfr.201800411
M3 - Article
C2 - 30192066
AN - SCOPUS:85054747859
VL - 62
JO - Molecular Nutrition and Food Research
JF - Molecular Nutrition and Food Research
SN - 1613-4125
IS - 22
M1 - 1800411
ER -