Abstract
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.
Highlights
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle
Chordoid glioma of the third ventricle is characterized by its stereotypic location in the anterior third ventricle and its chordoid cellular architecture composed of glial fibrillary acidic protein (GFAP)-positive tumor cells embedded within a myxoid matrix, often accompanied by a dense lymphoplasmacytic inflammatory infiltrate[1,2,3]
Chordoid gliomas were recently demonstrated to share expression of the homeobox transcription factor TTF-1 with the organum vasculosum of the lamina terminalis, suggesting a cellular origin of this neoplasm from these specialized ependymal cells located along the anterior wall of the third ventricle[6]
Summary
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Chordoid glioma of the third ventricle is characterized by its stereotypic location in the anterior third ventricle and its chordoid cellular architecture composed of glial fibrillary acidic protein (GFAP)-positive tumor cells embedded within a myxoid matrix, often accompanied by a dense lymphoplasmacytic inflammatory infiltrate[1,2,3]. Despite being histologically low-grade (classified as grade II in the 2016 WHO Classification of Tumors of the Central Nervous System) and well circumscribed without substantial invasion of surrounding brain tissue, chordoid gliomas are associated with substantial morbidity and mortality Their proximity and adherence to critical regional structures makes them difficult to safely resect. We report genomic analysis on a cohort of chordoid gliomas that was performed with the goal of identifying new diagnostic and prognostic biomarkers, as well as potential targets for molecularly tailored therapy for these rare brain tumors
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