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

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 (PKCa) 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. PKCaD463H mRNA levels are more abundant than wildtype PKC alpha transcripts, while PKC 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.