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

Shai Rosenberg (1, 2) , Iva Simeonova (1) , Franck Bielle (1, 3) , Maïté Verreault (1) , Bertille Bance (1) , Isabelle Le Roux (1) , Mailys Daniau (1) , Arun Nadaradjane (1) , Vincent Gleize (4, 1) , Sophie Paris (5, 1) , Yannick Marie (1, 6) , Marine Giry (1) , Marc Polivka (7) , Dominique Figarella-Branger (8, 9) , Marie-Hélène Aubriot-Lorton (10, 1) , Chiara Villa (11) , Alexandre Vasiljevic (12) , Emmanuèle Lechapt-Zalcman , Michel Kalamarides (13, 1) , Ariane Sharif (14) , Karima Mokhtari (1, 3) , Stefano Maria Pagnotta (15) , Antonio Iavarone (16) , Anna Lasorella (15) , Emmanuelle Huillard (1) , Marc Sanson (1, 6, 17)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 Sharett Institute of Oncology [Jerusalem, Israel]
3 Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]
4 ONERA - The French Aerospace Lab [Châtillon]
5 Biologie des Interactions Neurones / Glie
6 OncoNeuroTek [Paris]
7 Hôpital Lariboisière
8 Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone]
9 INP - Institut de neurophysiopathologie
10 CAPS - Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093]
11 Hôpital Foch [Suresnes]
12 Centre de Biologie et Pathologie Est - Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal [CHU Lyon]
13 Service de Neurochirurgie [CHU Pitié-Salpêtrière]
14 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
15 Herbert Irving Comprehensive Cancer Center
16 Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology
17 Service de neurologie 2 [CHU Pitié-Salpêtrière]

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 (PKC$\alpha$) and is mutated in a wide range of human cancers. However the hot spot PRKCA$^{D463H}$ mutation was not described in other tumors. PRKCA$^{D463H}$ is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKC$\alpha$$^{D463H}$ mRNA levels are more abundant than wild-type PKC$\alpha$ transcripts, whilePKC$\alpha$$^{D463H}$ is less stable than the PCK$\alpha$WT protein. Compared to PCK$\alpha$WT, the PKC$\alpha$$^{D463H}$ protein is depleted from the cell membrane. The PKC$\alpha$$^{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.

Keywords: Cancer genetics; OncogenesProtein; function predictions

Domains: Life Sciences [q-bio]

Shai Rosenberg, Iva Simeonova, Franck Bielle, Maïté Verreault, Bertille Bance, et al.. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nature Communications, 2018, 9 (1), pp.2371. ⟨10.1038/s41467-018-04622-w⟩. ⟨hal-01858239⟩