Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity’s unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.
Highlights
Diffuse intrinsic pontine gliomas (DIPG), brainstem tumors that diffusely involve the pons, are the most common type of brainstem gliomas (BSG) [1]
The first major breakthrough in defining the DIPG mutational landscape came in 2012, when studies on pediatric brain tumors using whole-genome and wholeexome sequencing (WES) reported that 70–84% of DIPG possess mutations in histone H3, and that these mutations were predictive of outcome [3, 24, 25]
This study reported two subgroups, which were characterized by upregulation of N-Myc or Hedgehog signaling through mRNA expression and DNA hypomethylation [85]
Summary
Diffuse intrinsic pontine gliomas (DIPG), brainstem tumors that diffusely involve the pons, are the most common type of brainstem gliomas (BSG) [1]. Despite 68 clinical trials using various adjuvant chemotherapeutic agents between 1984 and 2014, there has been no improvement in survival compared to radiation alone, and DIPG are currently the number one cause of brain tumor related death in children [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. The median survival of DIPG patients is only 10 months post diagnosis and
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