CNSC-61. NEURAL SIGNATURE DISTINGUISHES SILENT FROM OVERT PHENOTYPE IN CORTICOTROPIC PITNETS

Abstract Corticotroph pituitary neuroendocrine tumors (PitNETs) expressing adrenocorticotropic hormone (ACTH) can lead to Cushing’s disease (CD). In contrast, silent corticotroph PitNETs also produce ACTH but lack clinical or biochemical signs of hypercortisolism and have been associated with a more aggressive clinical course. The mechanisms underlying the divergent secretory behavior between overt and silent tumors remain incompletely understood. In overt cases, impaired negative feedback regulation has been linked to reduced glucocorticoid receptor (GR) expression, whereas silent tumors often retain GR expression and an intact feedback loop, potentially explaining the absence of overt hypercortisolism. We hypothesized that tumor-intrinsic neural signaling contributes to this differential hormonal activity. Using reference-based deconvolution of bulk DNA methylation profiles, we inferred cellular composition and classified TPIT-positive tumors according to neural lineage signatures. Samples were stratified into high- and low-neural subgroups based on hypomethylated CpG sites and expression of genes involved in synaptic integration. Clinically, silent corticotroph PitNETs presented with significantly larger tumor volumes. Methylation-based deconvolution revealed that silent phenotypes exhibited a significantly higher neural score, indicating increased neuronal lineage characteristics. These tumors also showed enriched neuronal and astrocytic signatures and reduced stem cell components. Immune deconvolution demonstrated that silent tumors were enriched in CD8⁺ T cells, neutrophils, and NK cells, contrasting with the immunosuppressive microenvironment in overt CD. Notably, peripheral basal cortisol levels negatively correlated with CD8⁺ T cell signatures, suggesting cortisol-mediated immune suppression in overt cases. These findings define silent TPIT-positive PitNETs as a distinct clinical and molecular subtype characterized and highlight the potential contribution of neural and immune cell interactions to the clinical behavior of corticotroph tumors.