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 PRKCAD463H 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 PRKCAD463H mutation was not described in other tumors. PRKCAD463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCαD463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCαD463H is less stable than the PCKαWT protein. Compared to PCKαWT, the PKCαD463H protein is depleted from the cell membrane. The PKCαD463H 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.

Details

Title
A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas
Author
Rosenberg, Shai 1   VIAFID ORCID Logo  ; Simeonova, Iva 2 ; Bielle, Franck 3 ; Verreault, Maite 2 ; Bance, Bertille 2 ; Isabelle Le Roux 2 ; Daniau, Mailys 2 ; Nadaradjane, Arun 2 ; Gleize, Vincent 2 ; Paris, Sophie 2 ; Marie, Yannick 4 ; Giry, Marine 2 ; Polivka, Marc 5 ; Figarella-Branger, Dominique 6 ; Marie-Hélène Aubriot-Lorton 7 ; Villa, Chiara 8 ; Vasiljevic, Alexandre 9 ; Lechapt-Zalcman, Emmanuèle 10 ; Kalamarides, Michel 11 ; Sharif, Ariane 12 ; Mokhtari, Karima 3 ; Pagnotta, Stefano Maria 13 ; Iavarone, Antonio 14 ; Lasorella, Anna 15 ; Huillard, Emmanuelle 2 ; Sanson, Marc 16 

1  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France; Gaffin Center for Neuro-oncology, Sharett Institute for Oncology, Hadassah – Hebrew University Medical Center, Jerusalem, Israel 
2  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France 
3  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France; Laboratoire R Escourolle, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France 
4  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France; Onconeurotek Tumor Bank, Institut du Cerveau et de la Moelle épinère—ICM, Paris, France 
5  Department of Pathology, AP-HP, Hôpital Lariboisière, Paris, France 
6  Pathology and Neuropathology Department, Assistance Publique-Hôpitaux de Marseille (AP-HM), CHU Timone, Marseille, France 
7  Department of Pathology and CRB Ferdinand Cabanne, CHU Dijon Bourgogne, Dijon, France 
8  Department of Pathological Cytology and Anatomy, Foch Hospital, Paris, France 
9  Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France 
10  Department of Pathology, CHU de Caen, Caen, France Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP Group, Caen, France 
11  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France; Service de Neurochirurgie, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France 
12  INSERM U1172, “Development and Plasticity of the Neuroendocrine Brain”, Lille, France 
13  Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Benevento, Italy; Institute for Cancer Genetics, Columbia University Medical Center, New York City, NY, USA 
14  Institute for Cancer Genetics, Columbia University Medical Center, New York City, NY, USA; Departments of Neurology and Pathology, Institute for Cancer Genetics, Irving Comprehensive Research Center, New York, NY, USA 
15  Institute for Cancer Genetics, Columbia University Medical Center, New York City, NY, USA; Departments of Pediatrics and Pathology, Institute for Cancer Genetics, Irving Comprehensive Research Center, New York, NY, USA 
16  Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, ICM, Paris, France; Onconeurotek Tumor Bank, Institut du Cerveau et de la Moelle épinère—ICM, Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Site de Recherche Intégrée sur le Cancer (SiRIC) “CURAMUS”, Paris, France 
Pages
1-9
Publication year
2018
Publication date
Jun 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04622-w
ProQuest document ID
2056747934
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.