Targeted next-generation sequencing of 13 chordoid gliomas of the third ventricle
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ABSTRACT:
PROVIDER: EGAS00001002733 | EGA |
REPOSITORIES: EGA
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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.
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Project description: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?) 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?D463H mRNA levels are more abundant than wild-type PKC? transcripts, while PKC?D463H is less stable than the PCK?WT protein. Compared to PCK?WT, the PKC?D463H protein is depleted from the cell membrane. The PKC?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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Project description:Chordoid glioma (ChG) is a characteristic, slow growing and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. We analyzed primary chordoid glioma samples by whole exome sequencing, RNAseq
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