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

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.

Biomarkers in tumors of the central nervous system – a review

“…The PRKCA D463H mutation has not been reported in other tumors, suggesting that it is a diagnostic hallmark for chordoid gliomas . However, different alterations in the PRKCA gene have been reported in two other CNS tumor entities; PRKCA D294G mutations in pituicytomas and the SLC44A1‐PRKCA gene fusions in papillary glioneuronal tumors .…”

“…Rosenberg et al. recently investigated 16 such tumors by whole‐exome and RNA sequencing and found that 15 cases harbored the same PRKCA D463H mutation. PRKCα is involved in a wide range of cellular processes, and can both act as a tumor suppressor and an oncogene.…”

“…Chordoid glioma of the third ventricle, WHO grade II, is a rare glial tumor with histology reminiscent of chordoma, mostly occurring in adults (mean age 46 years) (1). Rosenberg et al (100) recently investigated 16 such tumors by wholeexome and RNA sequencing and found that 15 cases harbored the same PRKCA D463H mutation. PRKCa is involved in a wide range of cellular processes, and can both act as a tumor suppressor and an oncogene.…”

Neuropathology in Pitié‐Salpêtrière hospital: Past, present and prospect

“…This rare tumor always expresses a missense mutation of the gene encoding proteinase K (PRKCA). Substrate analysis of this enzyme opens up targeted therapeutic perspectives . Metabolic studies offer other perspectives: oxidative metabolism is increased in glioma cells with a FGFR3‐TACC3 fusion and treatments directed against oxidative stress like metformin can induce tumor cell death …”

HDGF and PRKCA upregulation is associated with a poor prognosis in patients with lung adenocarcinoma

“…In our previous study, it was demonstrated that HDGF mRNA was highly expressed in LADC tissues and that increased HDGF levels promoted PRKCA expression by inhibiting miR-296-3p in LADC cells (11). PRKCA is a member of the PKC family, and upregulation of PRKCA has been reported in several types of cancer and has been found to regulate various cellular functions, including cell proliferation, survival and metastasis (15)(16)(17)(18). Although HDGF and PRKCA overexpression plays a pivotal role in NSCLC progression, the association between HDGF and PRKCA and clinical characteristics, as well as the prognostic effect of combined HDGF and PRKCA expression are not understood in LADC.…”