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

Hia S Ghosh; Ruchit V Patel; Elizabeth B Claus; L Nicolas Gonzalez Castro; Patrick Y Wen; Keith L Ligon; David M Meredith; Wenya Linda Bi

doi:10.1093/neuonc/noae258

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

Neuro Oncol. 2024 Nov 25:noae258. doi: 10.1093/neuonc/noae258. Online ahead of print.

Authors

Hia S Ghosh¹, Ruchit V Patel^{1

2}, Elizabeth B Claus^{1

3}, L Nicolas Gonzalez Castro^{4

5}, Patrick Y Wen⁵, Keith L Ligon⁶, David M Meredith⁶, Wenya Linda Bi¹

Affiliations

¹ Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts.
² Harvard Medical School, Boston, Massachusetts.
³ Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
⁴ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
⁵ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁶ Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.

PMID: 39584448
DOI: 10.1093/neuonc/noae258

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 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 1989-2020 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 was 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=0.93). 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 intermediate prognosis, refining IDHmut-astrocytoma classification.

Keywords: CDKN2A/B loss; IDH1/2-mutant astrocytoma; focal amplification; glioma; molecular risk stratification.