Childhood Cancer

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Defining the Molecular Mechanisms Underlying Pediatric Brain Tumor Penetrance

Institution: 
Washington University
Researcher(s): 
Nicole Brossier, MD/PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2019
Type of Childhood Cancer: 
Astrocytoma
Project Description: 

Background:

As we enter into an era of precision pediatric oncology, it is becoming increasingly important to identify the factors that underlie the risk of brain tumor development. This challenge is particularly relevant for individuals with cancer predisposition syndromes like neurofibromatosis type 1 (NF1), where 15-20% of children born with a germline NF1 gene mutation develop optic pathway gliomas (OPGs). Our inability to provide accurate risk assessment information for these young children leads to frequent sedated neuroimaging, suboptimal visual screening, and delays in instituting treatment for those at greatest risk. Leveraging emerging evidence from both human and animal studies suggesting not all NF1 gene mutations confer equal risk for OPG development, I now hypothesize that NF1 gene mutations differently increase the risk of optic glioma formation at the level of the cell of origin for these tumors.

Project Goal:

In this grant, I propose to perform a detailed analysis of the potential cells of origin for these tumors using a novel collection of NF1 mutant mice genetically engineered to harbor different NF1 patient germline NF1 gene mutations. Specifically, I plan to determine (a) which cells in the developing brain give rise to mouse optic gliomas and (b) the differential impact of the NF1 germline mutation on the capabilities of these cells to generate optic gliomas. Taken together, these experiments aim to determine how the germline NF1 gene mutation functions as a risk factor for pediatric brain tumor formation, relevant to future risk assessment strategies for NF1 and other pediatric brain cancer predisposition syndromes.