PSUN13 Transcriptional and epigenetic landscapes of adrenocortical tumors

Abstract Historically, our knowledge of adrenocortical tumorigenesis has been limited to clinical observations of genetic syndromes featuring benign and malignant adrenal disease. In the last two decades, the enormous boom in high-throughput approaches has transformed our understanding of adrenal pathophysiology. While benign adrenocortical tumors may be cured by surgery, adrenocortical carcinoma (ACC) continues to be associated with dismal clinical outcomes. Understanding the molecular pathogenesis of adrenocortical tumors and the programs that facilitate benign versus malignant trajectories is crucial for developing curative therapeutic approaches. Although numerous transcriptome, epigenome, and single cell datasets profiling physiologic adrenal cortex and adrenal tumors are publicly available, there is no analysis integrating the spectrum of physiologic to malignant disease. Through analysis of these datasets, including single center datasets and those published by ENCODE, ENSAT, and TCGA, we demonstrate that biologic processes involved in tissue differentiation are recurrently disrupted across tumorigenesis. While the dominant programs supporting benign tumors include intracellular signaling programs that stabilize steroidogenic identity, ACC is characterized by activation of proliferation, immune, and imprinting programs that restrict access to adrenocortical differentiation states. Taken together, these studies identify that loss of differentiation fidelity within the confines of putative cell of origin is the core determinant of benign versus malignant tumorigenesis in the adrenal cortex. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.