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Endocrine Abstracts (2022) 81 OC2.3 | DOI: 10.1530/endoabs.81.OC2.3

1Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France; 2Division of Endocrinology, Department of Medicine and Research Center, Centre Hospitalier de l’Université de Montréal (CHUM), Canada; 3Department of Endocrinology, Diabetes and Nutrition, Hôpital Haut Lévêque, CHU and University of Bordeaux, France; 4Endocrinology Unit, Department of Medicine, DIMED, Hospital-University of Padova, Italy; 5Inserm UMR 1052 / CNRS 5286 / Université Claude Bernard Lyon I, Centre de Recherche de Cancérologie de Lyon, France; 6Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Service d’Histologie, Embryologie et Cytogénétique, France; 7UMS 44 IBVB, Le Kremlin Bicêtre, France; 8Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique Moléculaire et d’Hormonologie, France; 9U1016 INSERM-Institut Cochin, France; 10US12 Ciphe, Parc Scientifique et Technologique de Luminy; 11Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital; 12Department of Endocrinology and Nutrition, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, France; 13Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, France; 14Normandie University, UNIROUEN, Inserm, DC2N, the Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Clinical Investigation Centre, CIC1404, Tumor BioBank-Centre for Biological Resources, France; 15CHR Orleans, Service d’Endocrinologie, Diabète et Nutrition, France; 16Department of Endocrinology, Diabetes and Nutrition, and PériTox, UMR-I 01 INERIS, University Picardie Jules Verne (UPJV), France; 17Service d’Endocrinologie, Hôpital Larrey, France; 18Endocrinology Unit, Department of Medicine, DIMED & Department of Neuroscience, Hospital-University of Padova, Italy; 19Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Netherlands; 20Univ Lille, CHU Lille, Inserm U1190, Institut Pasteur Lille, Chirurgie Générale et Endocrinienne, France; 21Department of Neuroscience, Faculté de Médecine, Université de Montréal, Centre de Recherche du Centre Hospitalier de l’Universiteé de Montreéal (CHUM), Canada; 22Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Anatomie et Cytologie Pathologiques, France; 23Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Chirurgie Digestive et Endocrinienne, France


Context: Primary bilateral macronodular adrenal hyperplasia (PBMAH) with glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing’s syndrome is caused by ectopic expression of GIP receptor in the adrenal tissue. The bilateral nature of this adrenal disease suggests germline genetic predisposition. We aimed to identify the molecular driver event responsible for ectopic GIP receptor expression in PBMAH.

Methods: We conducted an international, multicenter, retrospective, cohort study to collect blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for familial or sporadic GIP-dependent PBMAH with Cushing’s syndrome. We performed sequencing and copy-number analyses of blood and adrenal DNA. Adrenal samples from patients with PBMAH and Cushing’s syndrome without food-dependent cortisol production were used as controls. RNA-sequencing on adrenal samples was performed to study gene expression in GIP-dependent Cushing’s syndrome and in control samples. Functional in vitro studies were performed to study the impact of the genetic event identified in human adrenocortical H295R cells.

Results: 17 patients with familial or sporadic GIP-dependent PBMAH with Cushing’s syndrome were studied. We identified germline heterozygous pathogenic or likely pathogenic variants in the lysine demethylase 1A (KDM1A, or LSD1) gene in all 17 patients. We further identified a recurrent deletion of the short arm of chromosome 1 harboring the KDM1A locus in the adrenal lesions of affected patients. None of the 25 patients in the control group had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in the adrenal lesions. Transcriptome analysis of adrenals from affected patients revealed the global effect of KDM1A loss in adrenal tissue on gene transcription and identified differentially regulated genes, including those encoding for GIP receptor and some other G protein-coupled receptors involved in adrenal tumorigenesis and regulation of steroidogenesis. In vitro pharmacologic inhibition, silencing and knock-out by CRISPR-Cas9 genome editing of KDM1A led to an increase in GIP receptor transcripts and protein in H295R cells.

Discussion: We found that familial and sporadic GIP-dependent PBMAH is a genetic disease caused in 100% of cases studied by germline inactivating pathogenic variants of the KDM1A gene with a loss of heterozygosity of the second KDM1A locus in the adrenal lesions. This stepwise inactivation of KDM1A is suggestive of a tumor suppressor gene model of tumorigenesis. Uncovering of a common genetic mechanism of GIP-dependent PBMAH will enable genetic testing and counselling of affected patients and earlier detection of the disease in their relatives.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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