Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

Abstract

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages -not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the "classic" current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the "classic boxes" heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to "risk-group" stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

Potential New Therapies for Pediatric Diffuse Intrinsic Pontine Glioma

“…However, dysregulation of histone and cytosine methylation is unique to DIPGs, suggesting putative crosstalk between histone and DNA methylation pathways, thereby altering transcriptional activity (Bender et al, 2013). Thus, the finding, that DNA methylation profiles are associated with the K27M mutation regardless of tumor location, supports its role in driving the epigenetic phenotype and establishes a foundation for treatment with specific inhibitors of DNA methylation (Morales and Kieran, 2017). …”

Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery

“…Pediatric high-grade gliomas (pHGGs) constitute one-tenth of pediatric brain tumors [ 97 ]. They have a poor prognosis and are clinically and biologically different from the disease in adults [ 98 ].…”

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

“…Whereas adult cancers, particularly carcinomas, harbor high rates of gene mutations and fusion oncogenes, pediatric cancers are comparatively genomically "quiet" [13] . Epigenetic dysregulation, due to various mechanisms including mutations or aberrant imprinting, seems to be of particular import in many types of pediatric cancers (reviewed in [14][15][16][17][18][19][20] ). Additionally, segmental chromosomal changes, including segmental gains, losses, and translocations, are observed in multiple pediatric cancers and correlate with disease severity [21][22][23][24][25][26][27][28][29][30] , suggesting that the key genetic changes that lead to malignancy may occur in a more cataclysmic fashion than in adult cancers.…”