Molecular profile of Cushing's syndrome.

Cushing's syndrome comprises a heterogeneous group of disorders characterized by chronic excess of glucocorticoid release from adrenal glands, caused by altered adrenal function or by ACTH hypersecretion from pituitary or ectopic sources. Advances in high-throughput molecular profiling have substantially refined our understanding of the mechanisms underlying endogenous hypercortisolism. This chapter provides an integrated overview of the genetic, transcriptomic, and epigenetic alterations driving both ACTH-dependent and ACTH-independent forms of the disease. Hypothalamic-pituitary-adrenal axis regulation of cortisol homeostasis is controlled by complex feedback circuits involving glucocorticoid receptor signaling, transcriptional POMC regulation, and multilayered neuroendocrine inputs. Disruption of these regulatory networks represents a central event in disease pathogenesis. In corticotroph adenomas, recurrent somatic mutations in USP8, USP48, and BRAF converge on enhanced POMC transcription and ACTH secretion, while aggressive tumors frequently harbor alterations in TP53 and ATRX. Transcriptomic and spatial profiling reveal lineage-defined tumor identities alongside significant intratumoral heterogeneity, whereas epigenetic mechanisms-including DNA methylation, miRNA dysregulation, and chromatin remodeling-fine-tune hormone secretion and glucocorticoid feedback resistance. Ectopic ACTH-secreting neuroendocrine tumors exhibit a distinct molecular profile characterized by epigenetic reactivation of POMC through promoter hypomethylation and context-dependent transcriptional reprogramming, independent of canonical pituitary lineage factors. In contrast, ACTH-independent Cushing's syndrome is predominantly driven by constitutive activation of the cAMP/PKA pathway in adrenal lesions, most commonly through activating PRKACA mutations, with additional contributions from GNAS and CTNNB1. Adrenocortical carcinoma displays a more complex genomic landscape involving IGF2 overexpression, Wnt/β-catenin activation, and tumor suppressor alterations, reflecting its malignant phenotype. These molecular insights have direct clinical implications, enabling refined disease classification, improved prognostic stratification, and the identification of actionable therapeutic targets, including EGFR, MAPK, PKA, and glucocorticoid receptor-associated pathways. Collectively, the integration of multi-omics approaches is redefining the conceptual framework of Cushing's syndrome and paving the way toward precision medicine strategies in endocrine oncology.