SUN-458 Constitutional Duplication Of PRKACA Causes Primary Pigmented Nodular Adrenocortical Disease (ppnad) And Generates New Chromatin Interactions

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Abstract Disclosure: P. Vaduva: None. F. Violon: None. A. Chansavang: None. D. Hadjadj: None. G. Raverot: None. S. Espiard: None. A. Attia: None. L. Bouys: None. L. Thomeret: None. A. Weber Kuhn: None. K. Perlemoine: None. N. Chevalier: None. M. Vantyghem: None. M. Polak: None. M.C. Fragoso: None. A.S. Berthon: None. B. Ragazzon: None. A. Jouinot: None. E. Pasmant: None. J.Y. Bertherat: None. 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. Presentation: Sunday, July 13, 2025

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