Molecular and clinical prognostic factors in isocitrate dehydrogenase -mutant astrocytomas: Insights into biomarker-driven stratification

CDKN2A/B homozygous deletion (HD) defines isocitrate dehydrogenase (IDH)-mutant astrocytomas as World Health Organization (WHO) grade 4 and predicts aggressive tumor behavior. To identify clinical and molecular prognostic factors in these tumors, we conducted a retrospective multi-institutional study of 106 adult patients diagnosed with IDH-mutant astrocytomas (21 grade 2, 40 grade 3 and 45 grade 4). Tumors were classified using a custom DNA/RNA next-generation sequencing panel based on the 2021 WHO classification. This resulted in an upgrade to grade 4 in 10.3% of cases previously classified as grade II or III due to CDKN2A/B HD. Multivariate analysis identified CDKN2A/B HD (hazard ratio [HR], 1.76; P = .005), MET fusions/splicing variants (HR, 5.38; P = .002), and PDGFRA alterations (HR, 3.66; P = .009) as independent predictors for poor overall survival. The accumulation of these 3 genetic events was strongly associated with unfavorable survival (P < .001) and correlated with adverse clinical features, including lower Karnofsky Performance Status and higher Ki-67 indices. Our study validates the prognostic value of the WHO 2021 classification for IDH-mutant astrocytomas and demonstrates that MET and PDGFRA alterations are independent adverse prognostic factors, comparable to CDKN2A/B HD. Their cumulative burden enables refined molecular risk stratification to guide clinical management.