Canonical Amplifications and CDKN2A/B Loss Refine IDH1/2-mutant Astrocytoma Prognosis

Abstract Background Molecular features have been incorporated alongside histologic criteria to improve glioma diagnostics and prognostication. CDKN2A/B homozygous-loss associates with worse survival in IDH1/2-mutant astrocytomas (IDHmut-astrocytomas), the presence of which denotes a grade 4 tumor independent of histologic features. However, no molecular features distinguish survival amongst histologically defined grade 2 and 3 IDHmut-astrocytomas. Methods We assembled a cohort of patients ≥19 years old diagnosed with an IDHmut-astrocytoma between 1989 and 2020 from public datasets and several academic medical centers. Multivariate modeling and unbiased clustering were used to stratify risk. Results We identified 998 IDHmut-astrocytoma patients (41.5% female; 85.6% white). Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification were associated with reduced survival. Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived the longest (OS 205.7 months). Survival for grade 2/3 cases with either CDKN2A/B hemizygous-loss or focal amplifications (80.4, 88.7 months respectively) did not differ significantly from grade 4 cases with intact CDKN2A/B and no amplifications (91.5 months, P = .93). Grade 4 patients with either hemizygous or homozygous loss of CDKN2A/B had the shortest survival (OS 31.9, 32.5 months respectively), followed by grade 4 cases with intact CDKN2A/B and focal gene amplifications (OS 55.9 months). Integrating CDKN2A/B status and amplifications alongside histopathologic grade refined overall survival prediction. Unbiased clustering revealed 9 distinct molecular profiles, with differential survival. IDHmut-astrocytomas with any CDKN2A/B loss clustered together, regardless of grade, and exhibited the poorest outcomes. Conclusions Combining CDKN2A/B hemizygous-loss and focal gene amplifications reveals a group of IDHmut-astrocytoma patients with an intermediate prognosis, refining IDHmut-astrocytoma classification.