Neurofibromatosis type 1 (NF1) is a genetic disorder. Its clinical severity is extremely variable, even among members of the same family. The source of this clinical variation is unknown, and it may involve additional genetic changes or possibly environmental factors such as nutritional status. Very few studies have been conducted to determine the factors that influence tumor risk among NF1-affected individuals. Thus, prevention and treatment of cancers within NF1 are hindered by a lack of clear understanding of their causes. To achieve the long-term objective of reducing the burden of cancer for NF1 patients, it is first necessary to define causes and identify factors that modify risk in susceptible populations.

Evidence from observational studies suggests that prenatal vitamin supplementation during pregnancy may be protective for several childhood cancers. However, an increasing number of studies have shown that folic acid, a major component of prenatal vitamins, may in fact increase offspring tumor risk in certain genetically susceptible populations. The primary objectives of this project are to (1) establish whether maternal dietary folic acid level during the peri-gestational period (in and around pregnancy) can influence the rate and severity of NF1-related tumor development in offspring in a highly controlled experimental setting using a transgenic mouse model and (2) demonstrate feasibility of clinic-based recruitment of NF1 patients and their families for a comprehensive epidemiologic study of environmental and nutritional factors that modify risk of NF1-related tumors, with the long-term goal of conducting a large National Institutes of Health-funded epidemiologic study of NF1.

Our rationale is that if folic acid can modulate tumor incidence, the mechanism can then be determined, which will ultimately enhance understanding of how pediatric NF1 tumors develop from the earliest stages as a result of maternal nutrient levels and other environmental exposures. The significance of the proposed research is that it will help bridge a gap in knowledge from human studies by determining in a controlled experimental setting whether maternal dietary folic acid level can affect the rate and severity of NF1-related tumors in a well-characterized transgenic mouse model. In addition, very little epidemiologic data exists on the factors that might modify risk of NF1-related tumors. We propose to conduct pilot recruitment of NF1 families to establish the foundation for a large, comprehensive epidemiologic study of NF1.

If our hypotheses regarding the role of folic acid in NF1 tumor risk are correct, the next steps will be to (1) clarify the molecular mechanisms driving the association between folic acid and NF1 tumor development and (2) identify the time period during peri-gestation (i.e., conception, during pregnancy, post-natal) when folic acid is most important in driving carcinogenesis. The overall impact of these results will be an increased understanding of the role of peri-gestational folic acid intake in NF1-related tumor risk. Positive results would also provide insight into potential mechanisms driving the extreme variability in disease severity observed within families. It is estimated that there are over 105,000 people with NF1 in the United States. Knowledge about the potential risks of folic acid in the presence of genetic susceptibility and novel treatment options that could mitigate the severity of clinical course and comorbidities would have a substantial impact on the lives of patients. Furthermore, it could potentially lead to clinical trials within the next 10 years that could modify folate availability during critical time periods.

The proposed research is an important first step in gaining a basic understanding of whether maternal exposures during pregnancy play a role in the subsequent development of childhood cancer. This work is highly relevant to the public health of individuals affected with NF1. If the factors that cause malignancy can be defined, biological mechanisms can then be determined and targeted clinical strategies can be implemented to reduce the overall burden of malignancy in affected children.