A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle

Benjamin Goode; Gourish Mondal; Michael Hyun; Diego Garrido Ruiz; Yu-Hsiu Lin; Jessica Van Ziffle; Nancy M Joseph; Courtney Onodera; Eric Talevich; James P Grenert; Iman H Hewedi; Matija Snuderl; Daniel J Brat; Bette K Kleinschmidt-DeMasters; Fausto J Rodriguez; David N Louis; William H Yong; M Beatriz Lopes; Marc K Rosenblum; Nicholas Butowski; Tarik Tihan; Andrew W Bollen; Joanna J Phillips; Arun P Wiita; Iwei Yeh; Matthew P Jacobson; Boris C Bastian; Arie Perry; David A Solomon

doi:10.1038/s41467-018-02826-8

A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle

Nat Commun. 2018 Feb 23;9(1):810. doi: 10.1038/s41467-018-02826-8.

Authors

Benjamin Goode¹, Gourish Mondal¹, Michael Hyun¹, Diego Garrido Ruiz², Yu-Hsiu Lin³, Jessica Van Ziffle^{1

4}, Nancy M Joseph^{1

4}, Courtney Onodera⁴, Eric Talevich⁴, James P Grenert^{1

4}, Iman H Hewedi⁵, Matija Snuderl⁶, Daniel J Brat⁷, Bette K Kleinschmidt-DeMasters⁸, Fausto J Rodriguez⁹, David N Louis¹⁰, William H Yong¹¹, M Beatriz Lopes¹², Marc K Rosenblum¹³, Nicholas Butowski¹⁴, Tarik Tihan¹, Andrew W Bollen¹, Joanna J Phillips^{1

14}, Arun P Wiita^{2

3}, Iwei Yeh^{1

4}, Matthew P Jacobson², Boris C Bastian^{1

4}, Arie Perry^{1

14}, David A Solomon^{15

16}

Affiliations

¹ Department of Pathology, University of California, San Francisco, CA, 94143, USA.
² Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, USA.
³ Department of Laboratory Medicine, University of California, San Francisco, CA, 94107, USA.
⁴ Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, 94115, USA.
⁵ Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, 11591, Egypt.
⁶ Departments of Pathology and Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.
⁷ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
⁸ Department of Pathology, University of Colorado at Denver, Aurora, CO, 80045, USA.
⁹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
¹¹ Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
¹² Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
¹³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹⁴ Department of Neurological Surgery, University of California, San Francisco, CA, 94143, USA.
¹⁵ Department of Pathology, University of California, San Francisco, CA, 94143, USA. david.solomon@ucsf.edu.
¹⁶ Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, 94115, USA. david.solomon@ucsf.edu.

Abstract

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Cerebral Ventricle Neoplasms / enzymology*
Cerebral Ventricle Neoplasms / genetics
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Glioma / enzymology*
Glioma / genetics
Humans
Male
Middle Aged
Mutation, Missense
Phosphorylation
Protein Domains
Protein Kinase C-alpha / chemistry*
Protein Kinase C-alpha / genetics*
Protein Kinase C-alpha / metabolism
Third Ventricle / enzymology*

Substances

PRKCA protein, human
Protein Kinase C-alpha
Extracellular Signal-Regulated MAP Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding