Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

Although hotspot mutations in isocitrate dehydrogenase (IDH) genes are associated with favorable clinical outcomes in glioma, CDKN2A/B homozygous deletion has been identified as an independent predicator of poor prognosis. Accordingly, the 2021 edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has adopted this molecular feature by upgrading IDH-mutant astrocytoma to CNS WHO grade IV, even in the absence of glioblastoma-specific histological features-necrosis and microvascular proliferation. This new entity of IDH-mutant astrocytoma not only signifies an exception to the generally favorable outcome of IDH-mutant glioma, but also brings into question whether, and, if so, how, CDKN2A/B homozygous deletion overrides the anti-tumor activity of IDH mutation by promoting the proliferation of stem/neural progenitor-like cells. Understanding the mechanism by which IDH mutation requires intact tumor-suppressor genes for conferring favorable outcome may improve therapeutics.

Automated summary

CDKN2A/B homozygous deletion is associated with poor prognosis in glioma, but the new CNS WHO classification has upgraded IDH-mutant astrocytoma to grade IV, even without the histological features of glioblastoma. Understanding the mechanism of how IDH mutation and intact tumor-suppressor genes interact can improve therapeutics.