IDH-mutant astrocytoma with EGFR amplification—Genomic profiling in four cases and review of literature
Melissa Umphlett, Khawaja Hasan Bilal, Michael L. Martini, Abigail K. Suwala, Sadhna Ahuja, Omid Rashidipour, Isabelle M. Germano, Matija Snuderl, Peter Morgenstern, Nadejda M. Tsankova
Abstract
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.