Mutations of the MAPK/TSC/mTOR pathway characterize periventricular glioblastoma with epithelioid SEGA-like morphology–morphological and therapeutic implications
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Maria-Magdalena Georgescu1, Yan Li1, Mohammad Zahidul Islam1, Christina Notarianni2, Hai Sun2, Adriana Olar3 and Gregory N. Fuller4
1 Department of Pathology and Pathobiology and Feist-Weiller Cancer Center, Louisiana State University, Shreveport, LA 71103, USA
2 Department of Neurosurgery, Louisiana State University, Shreveport, LA 71103, USA
3 Department of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC 29425, USA
4 Department of Pathology, The University of Texas MD Anderson Cancer Center, TX 77030, USA
Keywords: epithelioid glioblastoma; SEGA-like; mTOR; MAPK; 4E-BP1
Received: May 13, 2019 Accepted: May 20, 2019 Published: June 18, 2019
Epithelioid glioblastoma is a recognized glioblastoma variant, recently added to the World Health Organization brain tumor classification, with similar prognosis as the classic variant and B-Raf V600E mutations in 50% of the cases. We identified a new subset of epithelioid glioblastoma with periventricular location and subependymal giant cell astrocytoma (SEGA)-like morphology. Genomic profiling of these tumors revealed driver mutations in NF1, subclonal mutations in TSC1, and a novel driver mutation in MTOR, suggesting upregulation of the MAPK/TSC1/mTOR pathway. Strong mTOR activation was confirmed by immunohistochemistry for the mTOR kinase target 4E-BP1. TSC1 and MTOR mutations have been previously described in low-grade glioma, such as SEGA, and focal cortical dysplasia, respectively, that display large cells with abundant cytoplasm, most likely resulting from the biogenetic signaling of mTOR. Unlike these, the mutations in SEGA-like glioblastoma occurred in the context of other genetic aberrations present in high-grade neoplasms, including in the CDKN2A/B, PIK3R1, PIK3CA and EGFR genes. For one patient with two temporally distinct specimens, the subclonal TSC1 pathogenic mutation was detected only in the specimen showing SEGA-like morphology, indicating requirement for mTOR activation as trigger for specific epithelioid/SEGA-like morphology. As FDA-approved kinase inhibitors are available and target many steps of the MAPK/mTOR pathway, recognition of this new subset of periventricular high-grade gliomas with clear phenotypic-genotypic correlates is essential for prompt biomarker testing and appropriate targeted therapeutic management of these patients.
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