Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Anne Lecoq , Constantine A. Stratakis (1) , Say Viengchareun (2) , Ronan Chaligné (3) , Lucie Tosca (4) , Antoine Tosca , Vianney Deméocq (5) , Mirella Hage , Annabel Berthon (6) , Fabio R. Faucz (1) , Patrick Hanna , Hadrien-Gaël Boyer (7) , Nicolas Servant (8) , Sylvie Salenave (9) , Gérard Tachdjian (4) , Clovis Adam (10) , Vanessa Benhamo (11) , Eric Clauser (12, 13) , Antoine Tachdjian , Jacques Young (2) , Marc Lombes (2) , Isabelle Bourdeau , Dominique Maiter (14) , Anne Guiochon-Mantel (15) , Antoine Tabarin (16) , Jérôme Bertherat (12, 13, 17, 18) , Hervé Lefebvre (7) , Wouter de Herder , Estelle Louiset (7) , André Lacroix (19) , Philippe Chanson (2) , Jérôme Bouligand (15) , Peter Kamenicky (2)

1 Section on Endocrinology and Genetics
2 Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique
3 Génétique et Biologie du Développement
4 Unité Fonctionnelle de Cytogénétique, Service d'Histologie Embryologie Cytogénétique
5 UBO UFR MSS - Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé
6 GReD - Génétique, Reproduction et Développement
7 DC2N - Différenciation et communication neuronale et neuroendocrine
8 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
9 Service d'endocrinologie
10 Hôpital Bicêtre
11 UR 830
12 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
13 Hôpital Cochin [AP-HP]
14 Endocrinology
15 Service de génétique moléculaire, pharmacogénétique et hormonologie
16 Departement Endocrinologie
17 IC UM3 (UMR 8104 / U1016) - Institut Cochin
18 Service de gynécologie et d'endocrinologie [CHU Cochin]
19 CEBC - Centre d'Études Biologiques de Chizé - UMR 7372

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.

Domaines: Interactions cellulaires [q-bio.CB]; Endocrinologie et métabolisme

Anne Lecoq, Constantine A. Stratakis, Say Viengchareun, Ronan Chaligné, Lucie Tosca, et al.. Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome. JCI Insight, 2017, 2 (18), ⟨10.1172/jci.insight.92184⟩. ⟨hal-01904330⟩