Molecular Stratification of Adult and Pediatric High Grade Gliomas

Abstract

Glioblastoma is the most common primary malignant brain tumor in adults. While less common in children, high grade glial and glioneuronal tumors are diagnosed in over 1000 pediatric patients per year in the United States. Given the marked advances in massively parallel sequencing over the last two decades, combined with advances in epigenetic studies such as methylation profiling, we now have a better understanding of the molecular features underlying and driving high grade gliomas in both adults and children. These molecular features are now used as part of the classification of these tumors, and aid in predicting their overall behavior and response to different therapeutic modalities. Herein, we describe the genetic characteristics of the most common high grade glial and glioneuronal tumors in adults and children, starting with the class-defining mutations, and moving into additional mutations commonly seen in the different tumor classes. As a broad category, high grade gliomas in adults can be divided into three main categories- (1) midline gliomas with H3 K27M mutations, (2) IDH-mutant glioblastomas, and (3) IDH-wildtype glioblastomas. Within children, there are many more categories. The histone mutation driven tumors are broadly divided into (1) midline gliomas with H3 K27M mutations and (2) hemispheric gliomas with H3 G34 R/V mutations. Additional high grade gliomas in children can be driven by many other drivers, including but not limited to amplifications of MYC/MYCN, PDGFRA, or EGFR. Infantile high grade gliomas represent another distinct category, driven by NTRK fusion or alterations in genes of the receptor tyrosine kinase signaling pathway, including ALK, ROS1, and MET. Finally, we briefly touch on some germline mutations that lead to an increased incidence of high grade gliomas, including those of neurofibromatosis type 1, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency/Turcot syndrome type 1.