A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas

• Published in: Nature communications Vol. 9; no. 1; pp. 2371 - 9
• Main Authors: Rosenberg, Shai, Simeonova, Iva, Bielle, Franck, Verreault, Maite, Bance, Bertille, Le Roux, Isabelle, Daniau, Mailys, Nadaradjane, Arun, Gleize, Vincent, Paris, Sophie, Marie, Yannick, Giry, Marine, Polivka, Marc, Figarella-Branger, Dominique, Aubriot-Lorton, Marie-Hélène, Villa, Chiara, Vasiljevic, Alexandre, Lechapt-Zalcman, Emmanuèle, Kalamarides, Michel, Sharif, Ariane, Mokhtari, Karima, Pagnotta, Stefano Maria, Iavarone, Antonio, Lasorella, Anna, Huillard, Emmanuelle, Sanson, Marc
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.06.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/109; 38/88; 45; 45/23; 45/70; 45/77; 631/114/2410; 631/208/68; 631/67/395; 82/29; Adult; Aged; Astrocytes; Brain tumors; Cell Proliferation; Cells, Cultured; Cerebral Ventricle Neoplasms - genetics; Cerebral Ventricle Neoplasms - metabolism; Female; Gene sequencing; Glioma; Glioma - genetics; Glioma - metabolism; Humanities and Social Sciences; Humans; Kinases; Life Sciences; Male; Middle Aged; multidisciplinary; Mutation; Point Mutation; Protein kinase C; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Tanycytes; Translation initiation; Tumorigenesis; Tumors; Cancer genetics; OncogenesProtein; function predictions
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04622-w

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA D463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA D463H mutation was not described in other tumors. PRKC A D463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCα D463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCα D463H is less stable than the PCKα WT protein. Compared to PCKα WT , the PKCα D463H protein is depleted from the cell membrane. The PKCα D463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis. Chordoid glioma is a slow growing diencephalic tumor whose mutational landscape is poorly characterized. Here, the authors perform whole-exome and RNA-sequencing and find that 15 of 16 chordoid glioma cases studied harbor the same PRKCA mutation which results in enhanced proliferation.