ECE2022 Oral Communications Young Investigator Awards (12 abstracts)
Integrated genomics reveals the molecular classification of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), correlating with specific profiles of illegitimate receptors expression and identifies KDM1A as the genetic cause of food-dependent Cushing syndrome
Lucas Bouys 1 , Florian Violon 1 , Anna Vaczlavik 1 , Giannone Gaetan 1 , Anne Jouinot 1 , Roberta Armignacco 1 , Isadora Pontes Cavalcante 1 , Annabel Berthon 1 , Eric Letouzé 2 , Patricia Vaduva 3 , Maxime Barat 1 , Bonnet Fideline 1 , Karine Perlemoine 1 , Christopher Ribes 1 , Mathilde Sibony 1 , Marie-Odile North 4 , Stéphanie Espiard 5 , Magalie Haissaguerre 6 , Igor TAUVERON 7 , Laurence Guignat 4 , Lionel Groussin 1 , Bertrand Dousset 1 , Martin Reincke 8 , Maria Candida Barisson Villares Fragoso 9 , Constantine A Stratakis 10,11,12 , Eric Pasmant 1 , Rossella Libe 1 , Guillaume Assié 1 , Bruno Ragazzon 1 & Jerome Bertherat 1
1Institut Cochin, Paris, France; 2Paris Artificial Intelligence Research Institute, Paris, France; 3CHU de Rennes, Rennes, France; 4Hôpital Cochin, APHP, Paris, France; 5CHRU de Lille, Lille, France; 6CHU de Bordeaux, Bordeaux, France; 7CHU de Clermont-Ferrand, Clermont-Ferrand, France; 8Klinikum der Universität München, Munich, Germany; 9University of Sao Paulo, Sao Paulo, Brazil; 10National Institute of Health, Bethesda, United States; 11Research Institute, ELPEN, Pikermi, Athens, Greece; 12Human Genetics & Precision Medicine, IMBB-FORTH, Heraklion, Crete, Greece
Introduction: In Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), cortisol secretion may be consecutive to physiological stimuli, through the illegitimate expression of G-protein coupled receptors (GPCR) in adrenocortical cells. The most characterized is the overexpression of GIP receptor (GIPR) leading to food-dependent Cushing syndrome (FDCS) but it has not been associated with the consecutive inactivation of ARMC5 responsible for 25% of PBMAH. This work aimed to investigate the molecular heterogeneity of PBMAH and its genetic causes.
Methods: A multi-omics analysis (transcriptome, methylome, miRNome, SNP array and exome sequencing) was performed on PBMAH tissues from 36 operated patients.
Results: The integrative analysis revealed three molecular groups with different clinical features: G1, 16 patients with PBMAH due to ARMC5 inactivating variants; G2, 6 patients with FDCS; and G3, 14 patients with a less severe phenotype. Exome sequencing identified 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 mRNA and protein levels (P=1.2×10-12 and P<0.01, respectively). G2 tumors are characterized by a specific pathological aspect including a large proportion of eosinophilic cells compared to G1 and G3 (P<0.001). The transcriptome analysis allows to show specific expression profiles of GPCR: G1/ARMC5 tumors showed a relative overexpression of the vasopressin receptors AVPR1A and AVPR1B compared to the two other groups (fold-change [FC] =7.39, P<0.001 and 3.98, P<0.001, respectively) but a lower expression of AVPR2 (FC=0.43, P=0.015); G2/KDM1A tumors showed a dramatic overexpression of GIPR compared to the two other groups (FC=105.02, P<0.001) but also of the adrenergic receptors ADRA1D and ADRA2A (FC=2.93, P=0.027 and 9.99, P<0.001, respectively) and of the LH/hCG receptor (LHCGR) (FC=12.20, P<0.001); G3 tumors showed a slight overexpression of the adrenergic receptors ADRA1B (FC=3.49, P=0.001) and in few tumors ADRA1D, AVPR2 and LHCGR were highly expressed suggesting molecular heterogeneity in G3.
Conclusion: This study reveals three distinct molecular groups of PBMAH with specific expression profiles of GPCR and identifies KDM1A inactivation as the genetic cause of FDCS. Besides GIPR, KDM1A inactivation seems to drive the overexpression of the LH/hCG receptor, potentially responsible for Cushing syndrome associated with pregnancy and menopause. KDM1A tumors present specific pathologic aspects including a large proportion of eosinophilic cells. ARMC5 and KDM1A genetic screening can now be offered for all PBMAH cases, opening the way to earlier diagnosis and improved management.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more