Perigestational Dietary Folic Acid Deficiency Protects Against Medulloblastoma Formation in a Mouse Model of Nevoid Basal Cell Carcinoma Syndrome

Abstract

Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the perigestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n = 126) were randomized to 1 of 3 diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) 1 mo prior to mating with Ptch1 ^+/− C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio = 0.47; 95% confidence interval 0.27–0.80) at 1 yr. No significant difference in incidence was observed between the control and high FA groups. Low maternal perigestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.

ACKNOWLEDGMENTS

The authors would like to thank Dr. Timothy K. Starr for review of this manuscript and assistance with the data analysis. All work was done at the University of Minnesota and was supported by National Institutes of Health (R03 CA141440 to J.R/D.L., T32 CA099936 to Julie A. Ross, and K05 CA157439 to Julie A. Ross); Children's Cancer Research Fund, Minneapolis, MN; and the University of Minnesota Brain Tumor Program, Minneapolis, MN.