Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy
Abstract
“Diffuse hemispheric glioma, H3 G34-mutant” (DHG) is being included as a new CNS grade 4 tumor type in the forthcoming 5th edition of the WHO Classification of Tumors of the Central Nervous System. DHG arises within the cerebral hemispheres of teenagers and young adults and can histologically resemble anaplastic astrocytoma, glioblastoma, or CNS embryonal tumor.1 Affected patients have a somewhat more favorable prognosis than both “Glioblastoma, IDH-wildtype” and “Diffuse midline glioma, H3 K27M-mutant,” but invariably suffer from disease recurrence and mortality using current treatment regimens.1–3 Exploration of genomically targeted therapeutic strategies is therefore needed. DHG is molecularly defined by a recurrent glycine to arginine or valine substitution at codon 35 of the histone H3.3 gene H3F3A, corresponding to amino acid 34 of the mature H3.3 protein. This p.G34R/V mutation results in steric change which blocks diand tri-methylation of lysine 36, thereby obstructing this posttranslational modification critical for glial differentiation.4,5 Additionally, DHG frequently have co-occurring mutational inactivation of TP53, and deleterious mutations in the ATRX chromatin remodeling gene associated with alternative lengthening of telomeres.1–3 However, the complete genomic landscape of this new tumor entity and potential targets for precision medicine therapy have yet to be fully defined. Here we report genomic characterization of 10 DHG tumors (Figure 1), which revealed…
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