Abstract
A putative molecular subtype of IDH-wildtype diffuse glioma with recurrent MAPK pathway alterations has recently been reported. By dimensionality reduction analysis of genome-wide methylation profiling, these tumors form a distinct methylation cluster of gliomas. Characterization of 47 tumors from 45 patients reveals that these gliomas are predominantly supratentorial in young adults, are highly infiltrative, and harbor mitogen-activated protein kinase (MAPK) pathway alterations with high rates of CDKN2A/2B deletion, PDGFRA amplification, MYCN amplification, NF1 variants, and BRAF alterations. The tumors' epigenetics are distinct from other adult and pediatric gliomas in the 2021 World Health Organization (WHO) classification. The histology of the gliomas most often demonstrates high-grade astrocytic features, but can be variable from tumor to tumor, as well as fall into a spectrum of histologic grades. Outcomes show considerable variability based on histologic grade and molecular features, supporting grading within this group of tumors to ensure optimal care choices on an individual patient basis. These unifying epigenetic, sequencing, and infiltrative astrocytic features allow the tumors to be considered diffuse astrocytoma, adolescent, and young adult-type, with MAPK alterations (DAYA).