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.
Subject(s)
Cerebral Ventricle Neoplasms/enzymology , Glioma/enzymology , Protein Kinase C-alpha/chemistry , Protein Kinase C-alpha/genetics , Third Ventricle/enzymology , Adult , Aged , Cerebral Ventricle Neoplasms/genetics , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Glioma/genetics , Humans , Male , Middle Aged , Mutation, Missense , Phosphorylation , Protein Domains , Protein Kinase C-alpha/metabolismABSTRACT
The activity of total, Mg++ dependent and Na+/K+ ATPase as well as the content of cAMP and cGMP in homogenates of human brain tumors have been investigated. Results are compared to values obtained from normal cortices. Na+/K+ ATPase and cAMP are decreased with a close relationship with the degree of malignancy, while Mg++ dependent activity is lower than in normal cortex but with no differences between the various tumors, and cGMP is unaffected. We conclude with a discussion on the metabolism of brain tumors and the suggestion of Na+/K+ ATPase activity as a marker of the malignancy of neoplastic growth.
Subject(s)
Astrocytoma/enzymology , Brain Neoplasms/enzymology , Oligodendroglioma/enzymology , Sodium-Potassium-Exchanging ATPase/metabolism , Astrocytoma/analysis , Brain Neoplasms/analysis , Cerebellar Neoplasms/enzymology , Cerebral Ventricle Neoplasms/enzymology , Cyclic AMP/analysis , Cyclic GMP/analysis , Humans , Oligodendroglioma/analysisABSTRACT
An electron-microscopic study of a choroid plexus papilloma from the lateral ventricle of a child revealed fine structural features typical of normal choroid plexus tissue. Utilizing the Ernst technique for demonstrating ouabain-sensitive, potassium-dependent phosphatase activity, Na-K-ATPase was localized along the basal and lateral plasmalemmas of the tumor epithelium but not along the ventricular surface (apical plasmalemma). This localization is similar to that found in normal choroid plexus epithelium of all species studied to date.
