Corticotropin (
ACTH)-independent macronodular adrenal hyperplasia (
AIMAH) is a heterogeneous condition in which
cortisol secretion may be mediated by gastrointestinal
peptide (GIP),
vasopressin,
catecholamines and other
hormones. We studied the expression profile of
AIMAH by genomic
cDNA microarray analysis. Total
RNA was extracted from eight tissues (three GIP-dependent) and compared to total
RNA obtained from adrenal glands from 62 normal subjects. Genes had to be altered in 75% of the patients, and be up- or downregulated at a cutoff ratio of at least 2.0; 82 and 31 genes were found to be consistently up- and downregulated, respectively. Among the former were regulators of transcription, chromatin remodeling, and cell cycle and adhesion. Downregulated sequences included genes involved in immune responses and
insulin signaling. Hierarchical clustering correlated with the two main
AIMAH diagnostic groups: GIP-dependent and non-GIP-dependent. The genes encoding the 7B2
protein (SGNE1) and WNT1-inducible signaling pathway
protein 2 (WISP2) were specifically overexpressed in the GIP-dependent
AIMAH. For these, and six more genes, the data were validated by semiquantitative amplification in samples from a total of 32 patients (the original eight, six more cases of
AIMAH, and 18 other adrenocortical
hyperplasias and
tumors) and the H295R
adrenocortical cancer cell line. In conclusion, our data confirmed
AIMAH's clinical heterogeneity by identifying molecularly distinct diagnostic subgroups. Several candidate genes that may be responsible for
AIMAH formation and/or progression were also identified, suggesting pathways that affect the cell cycle, adhesion and transcription as possible mediators of adrenocortical
hyperplasia.