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

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.

Molecular Landscape and Contemporary Prognostic Signatures of Gliomas

“…Notably, these new prognostic features did not reach statistical significance in the TCGA cohort, highlighting the population heterogeneity between non-TCGA and TCGA cohorts. 36–38 Moreover, we observed that being of white race emerged as a favorable prognostic indicator for IDH1/2 -mutant astrocytomas. This finding raises concerns about structural disparities in access to timely surgical and medical care or clinical trial enrollment, which may affect treatment outcomes.…”

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures

“…Alterations in the receptor tyrosine kinase EGFR occur frequently in IDH wild-type glioma but are rarely reported in IDH-mutant tumors 24 , 25 . Upon examination of four IDH-mutant tumors with NE and CE samples available (Fig.…”

Clinical roles of EGFR amplification in diffuse gliomas: a real-world study using the 2021 WHO classification of CNS tumors

“…The frequency of EGFR Amp was seldom depicted in IDH-mutant diffuse gliomas. Several previous studies included IDH-mutant GBM which is defined as IDH-mutant astrocytoma (WHO grade 4) currently, and examined EGFR Amp, with the ratio ranging from 3% to 16% ( Verhaak et al, 2010 ; Brennan et al, 2013 ; Li et al, 2019 ; Wong et al, 2021 ; Umphlett et al, 2022 ). Besides, a study by Bai et al found that 16 out of 86 (18%) IDH-mutant grade 2 to 3 gliomas were EGFR -amplified ( Bai et al, 2016 ).…”

“…Therefore, the prognostic role of EGFR Amp in the new entity of GBM under the 2021 WHO criteria needs further investigation. On the contrary, in IDH-mutant gliomas, EGFR alterations were less common and its prognostic value was under evaluated ( Bai et al, 2016 ; Umphlett et al, 2022 ). A study by Craig Horbinski et al used EGFR immunohistochemistry (IHC) and showed that EGFR expression failed to discriminate survival among astrocytic tumors ( Horbinski et al, 2011 ).…”