Molecular mechanisms and therapeutic targets in pediatric brain tumors

Abstract

Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

A comparative analysis of clinicopathological features and survival among early adolescents/young adults and children with low-grade glioma: a report from the Children’s Oncology Group

“…Advances in surgical and laboratory techniques could alter diagnostic classification and outcomes. In particular, given that molecular analysis is now widely performed for risk stratification and therapeutic decision making, we would have ideally analyzed all tumor tissues for specific genetic aberrations [30]. However, tumor tissues were not collected as part of the study and therefore unavailable for analysis.…”

Developmental origins and oncogenic pathways in malignant brain tumors

“…The SHH‐MB subgroup tumors are characterized by a variety of mutations in the SHH pathway including loss‐of‐function mutations in PTCH1 and SUFU , activating mutations in SMO , and amplifications of SHH , GLI2 , and MYCN (Jones et al, ; K. W. Liu et al, ; Pugh et al, ; Robinson et al, ). Recently, nonsense mutations in GNAS , which encodes a G‐protein Gα s , were detected in an aggressive form of SHH‐MB (He et al, ).…”

“…The most common genetic alteration in G3‐MB is MYC amplification (K. W. Liu et al, ). G3‐MB also has characteristic large‐scale genomic instability, including somatic copy number alterations, fusion of MYC and PVT1 genes, and loss of chromosome 17p and gain of 17q (known as i17q) (Jones et al, ; K. W. Liu et al, ; Northcott et al, ). Genomic structural rearrangement in a subset of G3‐MBs could lead to super‐enhancer relocation and activation of GFI1 family oncogenes to promote tumorigenesis (Northcott et al, ).…”

Pediatric Brain Tumor Genetics: What Radiologists Need to Know

“…Despite the exclusivity of histone gene mutations to pediatric HGGs, they are noted in only approximately one-half of cases of pediatric HGG, with the other half of the cases involving several smaller tumor subgroups, one of which is the IDH1 subgroup, which affects primarily the adolescent pediatric population. This subgroup of tumors is noted in less than 5% of pediatric HGGs and carries the most favorable prognosis among the pediatric population, with a median overall survival of 5 years (74,82,86,87,89).…”