A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle

• Published in: Nature communications 2018-02, Vol.9 (1), p.810-8, Article 810
• Main Authors: Goode, Benjamin, Mondal, Gourish, Hyun, Michael, Ruiz, Diego Garrido, Lin, Yu-Hsiu, Van Ziffle, Jessica, Joseph, Nancy M., Onodera, Courtney, Talevich, Eric, Grenert, James P., Hewedi, Iman H., Snuderl, Matija, Brat, Daniel J., Kleinschmidt-DeMasters, Bette K., Rodriguez, Fausto J., Louis, David N., Yong, William H., Lopes, M. Beatriz, Rosenblum, Marc K., Butowski, Nicholas, Tihan, Tarik, Bollen, Andrew W., Phillips, Joanna J., Wiita, Arun P., Yeh, Iwei, Jacobson, Matthew P., Bastian, Boris C., Perry, Arie, Solomon, David A.
• Format: Article
• Language: English
• Subjects: 13/95; 42/109; 45/22; 45/23; 45/44; 45/70; 631/67/395; 631/67/68; 692/4028/67/1059/602; 692/4028/67/1922; 692/4028/67/68; 82/51; 82/80; Adult; Aged; Astrocytes; Brain; Brain cancer; Brain tumors; Cerebral Ventricle Neoplasms - enzymology; Cerebral Ventricle Neoplasms - genetics; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Glial cells; Glioma; Glioma - enzymology; Glioma - genetics; Humanities and Social Sciences; Humans; Kinases; Male; Middle Aged; Missense mutation; multidisciplinary; Mutation; Mutation, Missense; Phosphorylation; Protein Domains; Protein kinase C; Protein Kinase C-alpha - chemistry; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Science; Science (multidisciplinary); Third Ventricle - enzymology; Tumors; Ventricle; Ventricles (cerebral)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-02826-8

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. Chordoid glioma is a rare low-grade brain tumor that originates from the anterior wall of the third ventricle where surgical resection is challenging; the clinical outcome of patients after subtotal resection or disease recurrence is poor. Here the authors identify a recurrent missense mutation in PRKCA that may serve as a potential therapeutic target in this uncommon brain cancer.