Sexually Dimorphic cAMP Signaling Impacts the Rate of Brain Tumors in Prepubertal Boys and Girls
- McDonnell Pediatric Cancer Center
Interdisciplinary Research Initiative
2/1/2012 - 1/31/2015
Incomplete understanding of why children get brain tumors hinders their cure. Neurofibromatosis 1 (NF1) is the most common genetic disease associated with childhood brain tumors (gliomas). The goal of this project is to better understand why some children with NF1 get gliomas and others do not. To achieve this goal we will examine subtle variations in DNA known as polymorphisms. Polymorphisms alter the activity of genes and can predispose to specific diseases. The hypotheses to be tested are that specific polymorphisms will; (i) be associated with glioma, (ii) identify genes involved in brain tumor development, and (iii) provide a tool to identify patients at risk for glioma prior to the onset of symptoms. In preliminary studies, polymorphisms were detected that were more common in children with NF1 and glioma than children with NF1 but no glioma. Furthermore, these polymorphisms imparted different glioma risk for boys and girls. Thus, it appears that sex of the patient impacts the risk for glioma in NF1. Aims: 1) Establish a polymorphism-based tool for identifying NF1 patients at risk for glioma using a newly formed international collaboration for efficient acquisition of DNA specimens and standard SNP array technologies 2) Determine the molecular basis for the sex bias in NF1-associated gliomagenesis using mouse models, which based on preliminary data appears related to differences in cAMP signaling in glial cells. Potential impact: Success in these aims will improve diagnostic and therapeutics for children with brain cancer as early as the next ten years. The focus on cAMP regulation and sex could generate new insights into the molecular causes of gliomas in both previously healthy children and children with NF-1. The international collaboration and the powerful resources of the Washington University Genome Center uniquely position us for success in these studies.