👤 Antoine Tabarin

GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations. Show less

Control of cortisol secretion by the abnormal expression of the gastric inhibitory polypeptide receptor (GIP-R) have been observed in some rare cases of ACTH-independent, food-dependent Cushing's syndrome (FD-ACS) due to adrenal adenoma (AA) or bilateral macronodular hyperplasia (AIMAH). This study was performed to determine the prevalence of GIP-R ectopic expression in ACS and its correlation with fasting cortisol levels. GIP-R expression was studied by RT-PCR in 30 unilateral adrenal tumors [16 AA and 14 adrenocortical cancer (AC)] and 8 AIMAH tissues. Fasting and postprandial cortisol levels were assayed, respectively, at 0800 and 1200 h in AA, AC, and AIMAH, and 1 h after a morning standard meal in 6 AIMAH patients. Similar expression of 2 GIP-R isoforms was observed in 1 of 16 AA, 0 of 14 AC, and 4 of 8 AIMAH as well as in the 4 insulinomas used as positive controls. In vitro study of the GIP-R-expressing AA showed stimulation of cortisol secretion and cAMP production by GIP. The fasting 0800-h plasma cortisol level was above 276 nmol/liter in all patients except 1 AA case and 1 AIMAH case, both of whom expressed GIP-R. In the 3 additional AIMAH cases that expressed the GIP-R, fasting plasma cortisol levels were above 276 nmol/liter. This study demonstrates that ectopic expression of GIP-R is rare in AA and is usually associated with the low fasting plasma cortisol levels that characterize FD-ACS. In contrast, GIP-R expression is frequent in AIMAH and might not always be associated with a low fasting plasma cortisol level. This suggests that maintenance of hypercortisolemia in GIP-R- expressing AIMAH does not always depend solely on GIP-R, and that simultaneous abnormal expression of other membrane receptors might be present. The expression of GIP-R could not be observed during malignant transformation of the adrenal cortex. This study highlighted the major role of cAMP alterations secondary to GIP-R ectopic expression in the pathophysiology of AIMAH and in some rare cases of well differentiated benign adrenocortical tumors. Show less