Mutations of the MAPK/TSC/mTOR pathway characterize periventricular glioblastoma with epithelioid SEGA-like morphology-morphological and therapeutic implications.

Maria-Magdalena Georgescu,Christina Notarianni,Adriana Olar,Hai Sun,Mohammad Zahidul Islam,Gregory N Fuller,Yan Li

doi:10.18632/oncotarget.27005

Abstract

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.

Highlights

Glioblastoma is the most frequent and aggressive glial tumor in adults, with an incidence of 3–4 cases per 100 000 population, and a median survival of 1.3 years [1]
We report here that a subset of periventricular glioblastoma exhibits an epithelioid subependymal giant cell astrocytoma (SEGA)-like appearance, and harbors mutations mapping to the mitogen-activated protein kinase (MAPK)/ tuberous sclerosis complex (TSC)/mTOR pathway, in addition to other pathogenic alterations detected in high-grade neoplasms
The most interesting aspect was that the TSC1 mutation co-existed with an already mutated background with driver mutations in epidermal growth factor receptor (EGFR) and PIK3CA, which, from the literature, are expected to lead to mTOR complex 1 (mTORC1) activation [25] (Figure 5)

Summary

Introduction

Glioblastoma is the most frequent and aggressive glial tumor in adults, with an incidence of 3–4 cases per 100 000 population, and a median survival of 1.3 years [1]. B-Raf V600E is well represented in predominantly cortical, youngonset, low-grade, morphologically-similar entities, such as ganglioglioma, pleomorphic xanthoastrocytoma and astroblastoma [4, 5]. These may be occasional components of epithelioid glioblastoma in some instances of anaplastic transformation of an initial lowgrade neoplasm [2, 6]. Another low-grade glioma (WHO grade I) with epithelioid morphology is subependymal giant cell astrocytoma (SEGA). SEGA almost always occurs in tuberous sclerosis patients with a germline mutation in the tuberous sclerosis complex (TSC) genes, and, as its name implies, it is always periventricular [1, 7]

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Conclusion