Advances in classification of pediatric brain tumors through DNA methylation profiling: from research tool to frontline diagnostic

摘要

Despite significant improvements in pediatric brain tumor therapy and outcome, too many children still die from disease, and too many survivors suffer significant sequelae as a result of conventional therapies. Molecular characterization of pediatric brain tumors has afforded tremendous insight into the basic biology and clinical management of these deadly childhood diseases. Genomic, epigenomic, and transcriptional profiling have facilitated the identification of significant heterogeneity among previously uniform disease entities. In particular, DNA methylation profiling has emerged as a robust tool for identifying key disease-specific subgroups that can exhibit distinct clinical outcomes. These approaches, which also complement classical histologic techniques, can suggest key mechanistic underpinnings of tumorigenesis and open the door for better informed and more tailored therapy. By leveraging the results of large-scale classifications of disease cohorts, novel driver mutations and pathways can be uncovered, enabling generation of faithful animal models, promoting targeted drug design, informing development biology, and ultimately translating to improved clinical management. In this review, the progress in epigenetic classification of common malignant pediatric brain tumors – medulloblastoma, ependymoma, high-grade glioma, atypical teratoid/rhabdoid tumor, and CNS embryonal tumors – will be discussed, and the potential role of DNA methylation profiling as a frontline diagnostic modality will be emphasized.