Cross-Cancer Characterization of CAMK2A Reveals Its Favorable Prognostic Association and Neuronal Signature Enrichment in Glioma

Background: Calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) is a neuron-enriched kinase that plays essential roles in synaptic signaling and neuronal differentiation. However, its clinical significance and biological relevance in glioma remain incompletely understood. This study aimed to systematically characterize CAMK2A across human cancers and investigate its prognostic significance and association with neuronal differentiation programs in glioma. Methods: An integrated multi-omics analysis was performed using pan-cancer transcriptomic, proteomic, genomic, DNA methylation, bulk RNA-sequencing, and single-cell RNA-sequencing datasets from TCGA, CPTAC, GTEx, CGGA, and other public resources. CAMK2A expression patterns, clinical associations, prognostic value, molecular characteristics, pathway activities, and cellular localization were systematically evaluated. Multiplex immunofluorescence staining of human glioma specimens was further performed to validate the protein-level expression patterns of CaMKII and the neuronal marker MAP2. Results:CAMK2A exhibited lineage-specific dysregulation across human cancers and was progressively downregulated during glioma progression. Higher CAMK2A expression was consistently associated with prolonged overall survival across multiple independent glioma cohorts and remained an independent favorable prognostic factor after adjustment for established clinicopathological and molecular variables. Functional enrichment analyses linked CAMK2A to neuronal differentiation, synaptic organization, calcium signaling, and neurotransmission-related pathways. Gliomas with high CAMK2A expression exhibited lower scores for several malignancy-associated pathways and enrichment of neuronal transcriptional signatures; these tissue-level associations do not distinguish tumor-intrinsic programs from normal neuronal admixture. Single-cell transcriptomic analyses further revealed preferential enrichment of CAMK2A in neuronal populations. Consistently, multiplex immunofluorescence demonstrated a coordinated reduction in CaMKII and MAP2 protein expression with glioma progression. Conclusions:CAMK2A represents a neuron-associated biomarker linked to preserved neuronal differentiation programs and favorable clinical outcomes in glioma. These findings support its potential value as a prognostic biomarker and provide further insight into the relationship between neuronal differentiation programs and glioma progression.