At the molecular level, IDH-mutant astrocytic LGGs typically harbor TP53 mutations and ATRX loss at baseline, but progression to grade 3/4 disease is driven by additional “late” genetic alterations, most notably bi-allelic CDKN2A/B deletion, which now defines a grade 4 IDH-mutant astrocytoma under the WHO CNS5 classification even in the absence of necrosis, and which is highly enriched at recurrence with sharply adverse prognostic impact; even hemizygous CDKN2A loss independently portends shorter OS in recurrent non-codeleted gliomas (161, 162). Here, ATRX is linked to central nervous system cancer.