Context: The mechanisms responsible for the ectopic adrenal expression of GIP receptor in GIP-dependent Cushing's syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing's disease (CD) or by GIP in GIP-dependent ACTH-independent macronodular adrenal hyperplasia (AIMAH) both lead to the induction of genes implicated in adrenal proliferation and steroidogenesis.

Objective: Identify genes differentially expressed specifically in GIP-dependent CS which could be implicated in the ectopic expression of GIP receptor.

Methods: We used the Affymetrix U133 plus 2.0 microarray oligochips to compare the whole genome expression profile of adrenal tissues from five cases of GIP-dependent bilateral AIMAH with CS, one case of GIP-dependent unilateral adenoma with CS, five cases of ACTH-dependant hyperplasias and a pool of adrenals from 62 normal individuals.

Results: After data normalization and statistical filtering, 723 genes with differential expression were identified, including 461 genes or sequences with a known functional implication, classified in 8 dominant functional classes. Specific findings include repression of perilipin, the over-expression of 13 GPCRs and the potential involvement of Rho-GTPases. We also isolated 94 probesets potentially linked to the formation of GIP-dependent nodules adjacent to the diffuse hyperplasia. These included probesets related to the linker histone H1 and repression of RXRa and CCND2. The expression profiles for 8 genes were confirmed by real-time RT-PCR.

Conclusion: This study identified an extensive series of potentially novel target candidate genes which could be implicated in the molecular mechanisms of ectopic expression of the GIP-receptor as well as in the multistep progression of GIP-dependent CS.