Abstract IA14: The unique genomic landscape of pediatric high-grade glioma

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for pediatric HGG ranges from 30 percent, for tumors arising in the cerebral cortex, to less than 10 percent for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Frequent recurrent somatic mutations in histone H3 distinguish the genetic drivers among pediatric and adult HGG. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs and 22 percent of non-brainstem HGG, where they occur predominantly in thalamic and other midline tumors. Strikingly, heterozygous H3F3A mutations encoding histone H3.3 G34R or G34V occur in approximately 14 percent of non-brainstem HGG, and are associated predominantly with cortical tumors arising in older children through young adulthood, suggesting a distinct developmental origin compared to the majority of tumors harboring K27M mutations. Recurrent mutations of the BMP receptor ACVR1/ALK2 have not been reported outside the brainstem, and are further restricted to the youngest DIPG patients, highlighting critical connections between development and gliomagenesis. Experiments to model the connections between oncogenic activity and developmental context will be discussed. Citation Format: Jon D. Larson, Andre B. Silveira, Lawryn H. Kasper, Helen R. Russell, Chunxu Qu, Peter J. McKinnon, Suzanne J. Baker. The unique genomic landscape of pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA14.