ECEESPE2025 Rapid Communications Rapid Communications 13: Adrenal and Cardiovascular Endocrinology Part 2 (6 abstracts)
Constitutional duplication of PRKACA causes primary pigmented nodular adrenocortical disease (PPNAD) and generates new chromatin interactions
Patricia Vaduva 1 , Florian Violon 1 , Albain Chansavang 2 , Djihad Hadjadj 2 , Gerald Raverot 3 , Espiard Stephanie 4 , Amina Attia 1 , Lucas Bouys 1 , Louis Thomeret 1 , Aliny Weber Kuhn 5 , Karine Perlemoine 1 , Nicolas Chevalier 6 , Marie-Christine Vantyghem 4 , Michel Polak 7 , Maria Candida Barisson Villares Fragoso 5 , Annabel Berthon 1 , Bruno Ragazzon 1 , Anne Jouinot 1 , Eric Pasmant 8 & Jérôme Bertherat 1
1Genomic and signaling of endocrine tumors team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, Paris, France; 2Genomic and epigenetics of rare tumors team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, Paris, France; 3Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; 4Department of Endocrinology, Diabetology, Metabolism and Nutrition, Lille University Hospital, Lille, France; 5Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, France; 6Department of Endocrinology, Diabetology and Reproductive medicine, Nice University Hospital, Nice, France; 7Department of Endocrinology, Gynecology and Pediatric diabetology, Necker Hospital, APHP, Paris, France; 8Department of genomic medicine of tumors and cancers, Cochin Hospital, APHP, Paris, France
JOINT2848
Objective: Constitutional duplications of the PRKACA gene locus (encoding the catalytic subunit of the Protein Kinase A) have been described in rare cases of Cushing’s syndrome due to bilateral nodular adrenocortical diseases (BNAD). The pathological description according to the current WHO definition of adrenal tumors still needs to be reported. The objective here was to evaluate the results of the systematic screening of PRKACA constitutive duplication in BNAD and to specify the associated hormonal and pathological phenotype.
Methods: Between 2020 and 2024, 781 index cases diagnosed with BNAD: bilateral macronodular adrenal disease (BMAD) (n=693) or primary pigmented nodular adrenocortical disease (PPNAD) (n=88) (14% of isolated PPNAD) were genotyped with a targeted Next Generation Sequencing (NGS) panel including the exonic and intronic flanking regions of the ARMC5, KDM1A, MEN1, PRKAR1A and PRKACA genes, or by whole genome sequencing. Familial screening was offered to relatives. In situ Hi-C libraries were generated from three patients’ tumors and chromatin conformation analysis were performed.
Results: Constitutional duplications of PRKACA were identified in 8 index cases and 7/11 screened relatives (sex-ratio=1 male/2.5 female), supporting the involvement of the PRKACA oncogene through a constitutional copy gain mechanism. The whole genome sequencing performed on 4 index cases did not find any other gene involved in human pathology in the duplicated region, nor any other alteration in genes implicated in adrenal pathology. PRKACA tandem duplications generated neo-Topologically Associating Domains (TADs) (150kb), self-interacting genomic regions, in patient derived tumor Hi-C maps compared to Micro-C data from human embryonic stem cell line. All index cases and 6/7 relatives had PPNAD responsible for ACTH-independent hypercorticism, diagnosed at a median of 21 years old (range 9-35) and treated by bilateral adrenalectomy. The resected adrenals contained micronodules, composed mainly of large eosinophilic cells containing lipofuscin vacuoles, separated by patches of atrophic cortex, making the diagnosis of PPNAD. Similar staining was found with PRKACA and PRKAR1A antibody in these nodules and adjacent cortex, whereas in patients with PRKAR1A pathogenic variants, PRKAR1A staining was decreased in the nodule, compared to adjacent cortex.
Conclusion: Constitutional duplication of PRKACA is causing PPNAD (9% of index cases with PPNAD in this cohort), but no other forms of BNAD. Immunohistochemistry may differentiate the genetic background of PPNAD (PRKAR1A pathogenic variants versus PRKACA duplications). PRKACA tandem duplications generated neo-TADs in patient derived tumor Hi-C maps, pointing to specific regions of gene expression dysregulation induced by PRKACA duplication in BNAD.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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