Benign adrenal
tumors cover a spectrum of lesions with distinct morphology and
steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical
tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical
tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays,
miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all
tumors. Pangenomic analysis identifies four distinct molecular categories: (1)
tumors responsible for overt Cushing, gathering distinct
tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2)
adenomas with mild autonomous
cortisol excess and non-functioning
adenomas, associated with
beta-catenin mutations; (3) primary macronodular
hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4)
aldosterone-producing
adrenocortical adenomas, apart from other benign
tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in
tumors with no or mild
cortisol secretion,
miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic
enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous
cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign
tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.