Pediatric high-grade glioma: biologically and clinically in need of new thinking

Abstract

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.

Keywords: DIPG; clinical trials; genomics; glioma; pediatric.

Fig. 1.

Biologically and clinically defined subgroups of pediatric infiltrating glioma. Specific, selective, recurrent, and mutually exclusive mutations in the genes encoding the histone H3.3 (H3F3A) and H3.1 (HIST1H3B, HIST1H3C) variants, along with BRAF V600E, mark distinct subgroups of disease in children and young adults. There are clear differences in location, age at presentation, clinical outcome, gender distribution, predominant histology and concurrent epigenetic and genetic alterations. The remaining half of tumors comprising these diseases harbor numerous, partially overlapping putative drivers or other (epi)genomic characteristics, but as yet do not form well-validated biological and clinical subgroups. The small proportion of children (mostly adolescents) with IDH1 mutations represent the lower tail of age distribution of an otherwise adult subgroup, and are excluded here.