Abstract
Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.
Highlights
Pediatric high-grade glioma is the leading cause of cancer death in children, with a median overall survival of less than one year [1]
H3K27M mutations are found in the vast majority of midline Pediatric high-grade glioma (pHGG), including over 80% of those in the pons and 60% of non-brainstem midline structures such as thalamus [8] and spinal cord [9]
This model led to spontaneous malignant brain tumor formation, with H3.3K27M driving hindbrain specificity of tumorigenesis and PDGFRA signaling driving pHGG identity
Summary
Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children, with a median overall survival of less than one year [1]. This dismal prognosis has remained stagnant for decades despite remarkable progress in other tumor types. IInn aaddddiittiioonn ttoo tthhee ddiissttiinncctt cclliinniiccaall pprreesseennttaattiioonn,, ttuummoorrss wwiitthh ssppeecciiffiicc hhiissttoonnee mmuuttaattiioonnss hhaavvee aa ddiissttiinncctt sseettoof fcocoococcucrurirnrignggengeetnicetailctearlatteiroantsiothnasttahpapteaapr ptoecaornttoribcountetrtiobtuhteeirtoontchoegiernoicnictyo.gFeonriceixtaym. In keeping with the relative abundance of research on H3.3K27M molecular mechanisms, the majority of preclinical models to date have focused on this particular oncohistone [20,21] (Table 1). H3.3WT, H3.3K27M and H3.1K27M tumors nestin+ NPCs nestin+ NPCs GFAP+ NPCs Olig2+ OPCs Olig2+ OPCs n/a
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