Glioblastomas arising in adults or children remain largely incurable. While gliomas in both age groups target common pathways, the frequency of specific mutations in each pathway differ between age groups. Although pediatric and adult glioblastoma have similar histopathological features, approximately half of all pediatric glioblastomas arise in the brainstem as diffuse intrinsic pontine gliomas (DIPGs), a disease that occurs almost exclusively in children. Recent studies from our group and others showed significant differences in the oncogenic drivers of glioma in different age groups. Most notably, frequent histone H3 mutations are specific to pediatric disease, with striking differences in the frequency and specific mutation in DIPG compared to non- brainstem pediatric glioblastomas. Thus, glioblastomas arise as the result of cooperating mutations in multiple pathways, some shared between adult and pediatric disease, and others unique to specific developmental contexts. In our unpublished genomic sequencing analysis of 112 pediatric high-grade gliomas, including 54 DIPGs, we identified somatic activating missense mutations in the BMP receptor ACVR1 in 32% of DIPGs, but not in non-brainstem high-grade gliomas, showing a unique selective advantage in the context of developing brainstem. We also identified gene fusions involving the kinase domain of each of the three neurotrophin receptor (NTRK) genes and five different N-terminal fusion partners. These fusions were found in 40% of non- brainstem high-grade gliomas from children under three years old, and at lower frequency in both DIPG and non-brainstem high-grade gliomas from older children. Recent studies from others also identified NTRK fusions in pediatric low-grade gliomas and adult glioblastomas. Thus, these alterations play a role in gliomagenesis in multiple developmental settings. This application investigates how specific mutations provide a selective advantage and contribute to tumorigenesis in select developmental settings, also exploring the contribution of PI3K signaling, which is disrupted in gliomas of all age groups. A full understanding of the mechanisms of transformation and downstream effects of these mutations are critical to the informed design of selective therapeutics for these deadly diseases.

Public Health Relevance

More than 70% of children with high-grade glioma will die within two years of their diagnosis. We identified recurrent mutations in ACVR1 and the NTRK family of neurotrophic receptors in pediatric high-grade glioma. Our goal is to understand how these mutations contribute to the development of glioma, and how these effects can be counteracted to improve therapy for these devastating childhood brain tumors.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA188516-01
Application #
8766268
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Mietz, Judy
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
Diaz, Alexander K; Baker, Suzanne J (2014) The genetic signatures of pediatric high-grade glioma: no longer a one-act play. Semin Radiat Oncol 24:240-7