KDM1A inactivation causes hereditary food-dependent Cushing syndrome |
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| Authors: | Anna Vaczlavik Lucas Bouys Florian Violon Gaetan Giannone Anne Jouinot Roberta Armignacco Isadora P Cavalcante Annabel Berthon Eric Letouzé Patricia Vaduva Maxime Barat Fidéline Bonnet Karine Perlemoine Christopher Ribes Mathilde Sibony Marie-Odile North Stéphanie Espiard Philippe Emy Jérôme Bertherat |
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| Institution: | 1. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France;2. Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;3. Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;4. Institut Curie, INSERM U900, MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Paris, France;5. Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris France;6. Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France;7. Department of Radiology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;8. Unit of Hormonology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;9. Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;10. Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Lille, France;11. Department of Endocrinology, CHR Orleans, Orléans, France;12. Department of Endocrinology, University of Bordeaux and CHU Bordeaux, Bordeaux, France;13. Department of Endocrinology, CHU Clermont Ferrand, Clermont-Ferrand, France;14. Department of Digestive and Endocrine Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;15. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany;16. Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil |
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| Abstract: | PurposeThis study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS.MethodsA multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing).ResultsThe integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10–12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS.ConclusionKDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management. |
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| Keywords: | Adrenocortical tumors ARMC5 Cushing syndrome GIPR KDM1A |
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