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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 
Abstract : 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.
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Submitted on : Monday, January 7, 2019 - 10:50:15 AM
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Rozenberg et al 2018 s41467-01...
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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, Nature Publishing Group, 2018, 9 (1), pp.2371. ⟨10.1038/s41467-018-04622-w⟩. ⟨hal-01858239⟩



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