The growing role of epigenetics in childhood cancers.

Abstract

Altered epigenetics is central to oncogenesis in many pediatric cancers. Aberrant epigenetic states are induced by mutations in histones or epigenetic regulatory genes, aberrant expression of genes regulating chromatin complexes, altered DNA methylation patterns, or dysregulated expression of noncoding RNAs. Developmental contexts of dysregulated epigenetic states are equally important for initiation and progression of many childhood cancers. As an improved understanding of disease-specific roles and molecular consequences of epigenetic alterations in oncogenesis is emerging, targeting these mechanisms of disease in childhood cancers is increasingly becoming important. In addition to disease-causing epigenetic events, DNA methylation patterns and specific oncohistone mutations are being utilized for the diagnosis of pediatric central nervous system (CNS) and solid tumors. These discoveries have improved the classification of poorly differentiated tumors and laid the foundation for future improved clinical management. On the therapeutic side, the first therapies targeting epigenetic alterations have recently entered clinical trials. Current clinical trials include pharmacological inhibition of histone and DNA modifiers in aggressive types of pediatric cancer. Targeting novel epigenetic vulnerabilities, either by themselves, or coupled with targeting altered transcriptional states, developmental cell states or immunomodulation will result in innovative approaches for treating deadly pediatric cancers.