Abstract 812: Maternal folic acid supplementation and risk of medulloblastoma in offspring
Authors: Johnson Kimberly J. , Allaei Raha , Hooten AJ , Largaespada David , Ross Julie 
Published: June 2012

Background: Epidemiological studies can give important insights into factors that modulate disease risk. However, the inherent limitations of observational studies make causal relationships difficult to infer. For example, several case-control studies have indicated that prenatal vitamins may protect against childhood brain tumors, including medulloblastoma, and folic acid (FA) is speculated to be the modulating factor. Using a murine model, we are testing whether low maternal dietary FA during the peri-gestational period increases medulloblastoma risk in offspring. We are using a well-defined transgenic mouse model of Gorlin syndrome, which is characterized by an autosomal dominant mutation in the PTCH1 gene. Heterozygous C57BL/6 strain Ptc1+/− mice have a medulloblastoma incidence of ∼40% at one year, making this transgenic model highly suitable for childhood brain cancer etiologic studies.

Methods. A total of 126 female wild-type C57BL/6 mice were randomized to one of three amino acid defined FA diets: 1) 0.3 mg/kg (low), 2) 2.0 mg/kg (control), and 3) 8.0 mg/kg (high), one month prior to mating with Ptc1+/− C57BL/6 males and maintained on their respective diets until weaning of their pups. Red blood cell (RBC) folate measurements were obtained from the dams at weaning and their association with the assigned dietary FA dose was determined using one-way ANOVA. The offspring have been genotyped and weaned heterozygotes are being followed for tumor development for one year. Interim hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards regression to examine the association between the assigned maternal dietary FA dose and offspring tumor incidence.

Results. In a total of 381 offspring, the overall Ptc1+/− genotype frequency is similar to previous reports with no significant differences between dietary groups (low: 40%, control: 40%, high: 42%). RBC folate concentrations in the dams at weaning increased significantly with increasing FA dose (p&lt;0.0001). Ptc1+/− offspring from each of the dietary groups have been followed for a mean of ∼6 months. To date, 25%, 35%, and 37% of Ptc1+/− offspring have developed tumors in the low, control, and high FA groups, respectively.Compared to the control group, the hazard for tumor development was non-significantly decreased in offspring in the low FA group (HR=0.7; 95% CI 0.3-1.4) and similar in the high FA group (HR=1.0; 95% CI 0.5-1.8).

Conclusions. In contrast to our hypothesis, these preliminary results indicate that higher doses of maternal dietary FA may increase offspring brain tumor incidence. We speculate that higher dietary FA levels during the peri-gestational period may influence brain tumor progression in mice predisposed to tumor development. The implications of these findings with respect to human populations will be discussed. Supported by R03CA141440, T32CA099936, and the Children's Cancer Research Fund, Minneapolis, MN.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2011-812