The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.

Chordoid glioma is a rare World Health Organization (WHO) Grade II brain tumor located near the third ventricle. Fewer than 100 cases have been reported in the literature, and surgery represents the main treatment option. Due to its typical location, complete surgical resection is uncommon, and the role of adjuvant radiotherapy remains controversial. Based on a case report, we performed a literature review focused on the potential role of adjuvant radiotherapy for chordoid glioma. We summarized data on patient characteristics, surgical approach and extent of resection, radiotherapy technique and dose, and clinical outcomes. A total of 18 patients from 14 studies were identified. Stereotactic treatments were used more frequently than conventional external beam radiotherapy, with doses ranging from 11.5-18 Gy and 45-59.4 Gy, respectively, and a median local control time of 26 months. Five patients developed disease recurrence after a median of 22.4 months. In the present case, the patient received adjuvant conventional radiotherapy (59.4 Gy/33 fractions) and remains alive after 12 months of follow-up with no major side effects. From the available evidence, modern radiotherapy may be considered a therapeutic tool that combines less invasive surgical procedures with improved local control, potentially reducing the risk of severe postoperative complications. Larger studies with longer follow-up periods are needed.

Chordoid glioma is a rare, slow-growing neoplasm of the central nervous system. To select an appropriate surgical approach, chordoid glioma should be differentiated from other third ventricle/suprasellar tumors, such as craniopharyngiomas. In this report, we present 3 cases of chordoid glioma. Magnetic resonance images of all cases showed a round or ovoid-shaped tumor with significant enhancement with contrast medium on T1-weighted images. Moreover, preoperative T2-weighted coronal images revealed high intensity along the bilateral hypothalamus. The tumor was removed using the trans-lamina terminalis approach. Gross total resection and partial resection were achieved in 2 cases and 1 case, respectively. Immunohistochemical staining showed strong positivity for glial fibrillary acidic protein and thyroid transcription factor-1, indicating a chordoid glioma. Tumor cells also showed diffuse immunoreactivity for matrix metalloproteinase 9, indicating that the high intensity was caused by vasogenic edema. High-intensity bilateral hypothalamus on T2-weighted images is a unique feature of chordoid glioma and plays an important role in improving clinical outcomes through local tumor control and functional preservation.

Chordoid glioma (ChG) is a rare, low-grade brain tumor characterized by a novel recurrent point mutation, D463H, in the kinase domain of protein kinase C alpha (PKCα). The mutation is invariably an Asp to His substitution, suggesting it endows a unique function beyond catalytic inactivation associated with other cancer-associated PKCα mutations. Here we use in vitro and in cellulo activity assays to show that PKCα D463H is catalytically inactive, functions as a dominant-negative mutant to suppress endogenous PKC and uniquely rewires the cellular interactome. Specifically, phosphoproteomic, proximity labeling, and co-immunoprecipitation mass-spectrometry data from cells overexpressing PKCα D463H identify altered phosphorylation of substrates and binding to multiple proteins involved in cell-cell junctions compared to WT enzyme. Lastly, single nuclei RNAseq reveals that ChG derives from specialized tanycytes. Our data suggest that this disease-defining, fully penetrant mutation promotes neomorphic non-catalytic scaffolding to impair cell junction function.

Chordoid glioma is an extremely rare, slow-growing brain tumor. This report discusses the clinical presentation, imaging characteristics, surgical approach, histopathology, and prognosis. The review of literature provides an overview focusing on diagnostic challenges and treatment strategies. A 21-year-old male presented with progressive blurring of vision, headache and intermittent convulsive seizures over a period of 2 months. Computerized tomography and magnetic resonance imaging revealed a mass in the right lateral ventricle, possibilities of central neurocytoma or ganglioglioma. Surgical resection was performed, and histopathological examination confirmed the diagnosis of chordoid glioma through a combination of histological and immunohistochemical analyses. Chordoid glioma is a distinct clinicopathologic entity, recognized for its unique histological and immunohistochemical features. It is crucial to differentiate chordoid gliomas from other neoplasms due to differences in treatment approaches and prognosis. Chordoid glioma, although rare, should be considered in the differential diagnosis of lateral ventricular tumors, especially in young adults presenting with visual and neurological symptoms. Early diagnosis and surgical intervention are crucial for improving outcomes.