Adrenal Gipr Expression and Chromosome 19q13 Microduplications in Gip-Dependent Cushing’s Syndrome

Presentation Number: OR02-7
Date of Presentation: April 4th, 2017

Anne-Lise Lecoq1, Constantine A Stratakis2, Say Viengchareun3, Ronan Chaligné4, Lucie Tosca5, Vianney Deméocq6, Mirella Paul Hage7, Annabel Sophie Berthon8, Fabio R. Faucz9, Patrick Hanna10, Hadrien-Gael Boyer11, Nicolas Servant4, Sylvie Salenave12, Gérard Tachdjian5, Clovis Adam5, Vanessa Benhamo4, Eric Laurent Clauser13, Anne Mantel14, Jacques Young15, Marc Lombes3, Isabelle Bourdeau16, Dominique Maiter17, Antoine Tabarin18, Jerome Yves Bertherat19, Herve Lefebvre20, Wouter W. de Herder21, Estelle Louiset20, Andre Lacroix16, Philippe Chanson22, Jérôme Bouligand23 and Peter Kamenický*12
1INSERM U693 - Faculté de Médecine Université Paris Sud, Le Kremlin Bicêtre, France, 2National Institutes of Health, Bethesda, MD, 3Inserm U1185, Le Kremlin-Bicêtre, France, 4Institut Curie, 5APHP, 6INSERM, 7Inserm, PARIS, France, 8National Institutes of Health (NIH), Bethesda, MD, 9National Institute of Health, Bethesda, MD, 10INSERM U1169, LE KREMLIN BICETRE, France, 11INSERM U982, Institute for Biomedical Research and Innovation, University of Rouen, Mont Saint Aignan, France, Mont Saint aignan, France, 12Univ Paris-Sud, Université Paris-Saclay; Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, France, 13Paris-Descartes University , APHP, Cochin, PARIS, France, 14Laboratory of Molecular Genetics, Pharmacogenetics and Hormonology, University Hospital of Bicetre, LE KREMLIN BICETRE, France, 15AP-HP, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France, 16Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada, 17Université Catholique de Louvain, Brussels, Belgium, 18University Hospital (CHU) of Bordeaux, Pessac, France, 19INSERM U 1016, Cochin Institute, Paris Descartes University, Paris, France, 20Normandie University, UNIROUEN, INSERM U982, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, ROUEN, France, 21Erasmus Medical Center, Rotterdam, Netherlands, 22APHP, Le Kremlin-Bicetre, FRANCE, 23Hôpital Bicêtre Assistance Publique Hôpitaux de Paris, Le Kremlin Bicêtre, France

Abstract

Background 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.

Methods 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. We studied in vitro the functional consequences of the novel genomic environment of GIPR identified in an adrenocortical adenoma.

Results GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of 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 three patients. In two 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.

Conclusions Ectopic GIPR expression in adrenocortical adenomas and in bilateral macronodular adrenal hyperplasias occurs constantly from a single GIPR gene allele. This monoallelic pattern of aberrant GIPR expression was associated in three adrenal lesions with genomic gain in 19q13.32 containing the GIPR gene, and in two lesions with chromosomal rearrangements, creating a genomic environment favoring GIPR transcription.

 

Nothing to Disclose: ALL, CAS, SV, RC, LT, VD, MPH, ASB, FRF, PH, HGB, NS, SS, GT, CA, VB, ELC, AM, JY, ML, IB, DM, AT, JYB, HL, WWD, EL, AL, PC, JB, PK