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

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 (PKC?). 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.

SUBMITTER: Goode B

PROVIDER: S-EPMC5824822 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Goode Benjamin B Mondal Gourish G Hyun Michael M Ruiz Diego Garrido DG Lin Yu-Hsiu YH Van Ziffle Jessica J Joseph Nancy M NM Onodera Courtney C Talevich Eric E Grenert James P JP Hewedi Iman H IH Snuderl Matija M Brat Daniel J DJ Kleinschmidt-DeMasters Bette K BK Rodriguez Fausto J FJ Louis David N DN Yong William H WH Lopes M Beatriz MB Rosenblum Marc K MK Butowski Nicholas N Tihan Tarik T Bollen Andrew W AW Phillips Joanna J JJ Wiita Arun P AP Yeh Iwei I Jacobson Matthew P MP Bastian Boris C BC Perry Arie A Solomon David A DA

Nature communications 20180223 1

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 muta ...[more]

PMID: 29476136

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Project description:A highly penetrant heterozygous mutation in PRKCA was found recently in chordoid glioma. To establish whether this mutant of PKCapha was a driver of tumour formation or maintenance in vivo, knock-in mice were generated. The constitutive, heterozygous expression of the Prkca D463H mutant in mice provoked the development of bilateral hindlimb chondrosarcomas and early neonatal mortality. The lack of activity of the D463H mutant was not the trigger of the phenotype as heterozygous knock-in of the related inactivating mutation D463N produced offspring indistinguishable from parental strains. Moreover, this surprising distinction between D463H and D463N mutations did not reflect a selective lack of dominance for the D463N mutation over the wild type (WT) allele since homozygous expression of this mutation was phenotypically WT. In cell culture, the D463H mutant expression, localisation and downregulation behaviours closely mimicked that of the WT, with the D463N mutant displaying some subtle differences. Biochemically, both the D463H and D463N mutants were shown to be inactive, although based on thermal shift assays the D463N mutant had reduced ATP affinity compared to WT or D463H proteins. Using induced transcriptional changes as a functional readout, altered mRNA expression indicates that the D463H acts as a dominant gain-of-function PKC mutant, despite a complete lack of intrinsic kinase activity; transcriptional changes induced by the D463N mutant were distinct from both the WT and D463H mutant. These findings suggest a model in which there is a non-catalytic effector function of PKCalpha which it is presumed operates through protein-protein interactions, as evidenced here by TurboID proximity labelling. The penetrant selection of the specific inactivating D463H mutation in chordoid glioma and the distinction with the D463N mutation indicates that this is conformationally sensitive. The properties characterised suggest this is driven by ATP binding and by inference, in this tissue context, the catalytic activity of this kinase acts as an autoregulatory negative feedback control.

Dataset Information

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

Publications

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

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