IDH-mutant astrocytoma with EGFR amplification-Genomic profiling in four cases and review of literature.

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Abstract EGFR amplification is associated with aggressive glioma behavior and regarded as a molecular feature of glioblastoma. Although rare, IDH-mutant astrocytomas with EGFR amplification exist but remain poorly understood. We report the clinical and molecular profile of four grade 4 IDH-mutant astrocytomas with EGFR amplification, evaluated using histology, DNA sequencing, cytogenetics, and DNA methylation profiling. Other alterations included ATRX, TP53, and PIK3CA mutations; CDKN2A/B loss; PDGFRA+KIT amplifications; and MGMT methylation in two cases. None disclosed microsatellite instability. DNA methylation confidently classified all tumors as “IDH-mutant High-Grade Astrocytoma” (0.99 0.997, 0.98, and 0.99 scores), despite their EGFR-amplified status. Literature review indicated EGFR amplification occurs within 8-19% of IDH-mutant gliomas, with significantly lower overall survival only in the co-presence of CDKN2A/B loss and MET amplification. Our report suggests IDH-mutant astrocytomas with EGFR amplification are under-recognized and that EGFR amplification status alone does not carry diagnostic or prognostic significance in these tumors.