H3.3 (H3F3A) variant at G34

The H3.3 G34 subtype arises from H3.3 glycine 34 to arginine/valine (G34R/V) variants.[36,37] This subtype presents in older children and young adults (median age, 14–18 years) and arises exclusively in the cerebral cortex.[36,37] H3.3 G34 cases commonly have variants in TP53 and ATRX (95% and 84% of cases, respectively, in one large series) and show widespread hypomethylation across the whole genome. In a series of 95 patients with the H3.3 G34 subtype, 44% of patients also had a variant in PDGFRA at the time of diagnosis, and 81% of patients had PDGFRA variants observed at relapse.[47]

Patients with H3F3A variants are at high risk of treatment failure,[48] but the prognosis is not as poor as that of patients with histone 3.1 or 3.3 K27M variants.[37] O-6-methylguanine-DNA methyltransferase (MGMT) methylation is observed in approximately two-thirds of cases, and aside from the IDH1-altered subtype (see below), the H3.3 G34 subtype is the only pediatric high-grade glioma subtype that demonstrates MGMT methylation rates exceeding 20%.[10]