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Updated: Mar 30, 2026
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
Expanding the molecular grading criteria in IDH-mutant astrocytoma
Michael Christian Virata1, Jorge Samanamud1, Cheyanne C Slocum1
1Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York (M.C.V., J.S., C.C.S., S.K., P.N., S.H., C.M.D., K.C., M.V., E.M., Y.N., M.U., T.J.S.H., J.M.W., N.M.T., T.E.R.).
Background:
IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers.
Methods:
We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367).
Results:
The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months).
Conclusions:
The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.
