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

Shai Rosenberg; Iva Simeonova; Franck Bielle; Maïté Verreault; Bertille Bance; Isabelle Le Roux; Mailys Daniau; Arun Nadaradjane; Vincent Gleize; Sophie Paris; Yannick Marie; Marine Giry; Marc Polivka; Dominique Figarella-Branger; Marie-Hélène Aubriot-Lorton; Chiara Villa; Alexandre Vasiljevic; Emmanuèle Lechapt-Zalcman; Michel Kalamarides; Ariane Sharif; Karima Mokhtari; Stefano Maria Pagnotta; Antonio Iavarone; Anna Lasorella; Emmanuelle Huillard; Marc Sanson

doi:10.1038/s41467-018-04622-w

Journal articles

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 et de la Moëlle Epinière = Brain and Spine Institute

2 Sharett Institute of Oncology [Jerusalem, Israel]

3 Laboratoire de Neuropathologie Raymond Escourolle

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 - U1172 Inserm - 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]

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.

Keywords : Cancer genetics OncogenesProtein function predictions

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Journal articles

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Life Sciences [q-bio]

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Rozenberg et al 2018 s41467-01...

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

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