A Novel C19orf47-AKT2 Chimeric RNA Generated by Cis-Splicing of Adjacent Genes Is Associated With Glioblastoma Prognosis.

Objective: Malignant gliomas pose significant therapeutic challenges. This study aimed to identify and characterize a novel chimeric RNA in glioma and assess its clinical and functional significance for precision treatment.

Methods: The C19orf47-AKT2 chimeric RNAs were identified through RNA sequencing and validated by polymerase chain reaction. Their expression in tumor core and peritumoral tissues was quantified and compared via quantitative polymerase chain reaction, whereas their prognostic significance in glioblastoma was assessed using Kaplan-Meier analysis. The formation mechanism was investigated through genomic analysis, and western blotting was performed to assess fusion protein translation. The CCK-8 assay was performed to assess the chimeras' effect on glioma proliferation.

Results: C19orf47-AKT2 chimeric RNAs were detected in 88.9% (144/162) of glioma core tissues, significantly higher than in peritumoral tissues (65.2%, 30/46, p < 0.001). Quantitative analysis showed no significant expression difference between variants in peritumoral tissues, but the C19orf47e9-AKT2e2 variant was significantly more abundant in tumor core tissues. High expression of this variant correlated with poor prognosis in glioblastoma patients. Mechanistically, C19orf47-AKT2 chimeras were generated via cis-splicing of adjacent genes, without DNA rearrangement. Although Western blot confirmed the translation of C19orf47e9-AKT2e3 into a fusion protein in 293 T cells, no endogenous fusion protein was detected in glioblastoma tissues or cells. Functional assays demonstrated that downregulation of C19orf47-AKT2 chimeras significantly suppressed the proliferation of patient-derived glioblastoma cells.

Interpretation: This study identifies novel C19orf47-AKT2 chimeras formed through cis-splicing, which might function as noncoding RNAs to promote glioblastoma proliferation. These chimeras may serve as potential prognostic markers and therapeutic targets in gliomas.