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Endocrine Abstracts (2023) 90 RC5.3 | DOI: 10.1530/endoabs.90.RC5.3

ECE2023 Rapid Communications Rapid Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)

Study of somatic molecular heterogeneity in bilateral macronodular adrenocortical disease (BMAD) by NGS panel in a cohort of 26 patients

Florian Violon 1,2 , Lucas Bouys 1,3 , Giannone Gaetan 1 , Patricia Vaduva 1 , Karine Perlemoine 1 , Annabel Berthon 1 , Bruno Ragazzon 1 , Mathilde Sibony 1.2 & Jerome Bertherat 1,3

1Cochin Institute, Endocrine Tumor Signaling Pathway and Genomic, Paris, France; 2Cochin Hospital, Pathology, Paris, France; 3Cochin Hospital, Endocrinology, Paris, France

Introduction: Bilateral macronodular adrenal disease (BMAD) is a genetically heterogeneous disease that can be caused by ARMC5 or KDM1A alterations. Indeed, a germline and somatic event leading to a bi-allelic inactivation of ARMC5 or KDM1A are responsible for 20 and 1% of BMAD cases, respectively. Genetic analysis identified three molecular groups: ARMC5, KDM1A and no genetic cause known to date. Although there is a high heterogeneity in the somatic events identified in the different nodules from ARMC5 mutated patients, the somatic events were never studied on several nodules from KDM1A mutated patients. The aim of this work was to study the mutational profile of different nodules from the same patient in a cohort of BMAD to describe the somatic alterations of patients with pathologic germline ARMC5 or KDM1A variants and to look for potential pure somatic genetic alterations in patients with no known genetic cause. Patients and methods26 patients underwent surgery for BMAD at the Cochin Hospital between 2006 and 2021. 148 DNA samples were extracted from formalin-fixed and paraffin-embedded material after macrodissection. Qualified DNA were sequenced by Illumina NGS sequencing for a panel of 7 genes: ARMC5, GNAS, KDM1A, PDE8B, PDE11A, PRKACA and PRKAR1A.

Results: For 3 patients all DNA samples (n=23) were too degraded to be analyzed. Out of the 7 patients with a germline pathological ARMC5 variant, 6 had 2 to 8 pathological somatic ARMC5 variants for 3 to 10 nodules sampled. The last patient had one unique somatic event detected on 5 nodules. Out of the 3 patients with a germline pathological KDM1A variant, each nodule had a loss of heterozygosity. Out of the 13 patients without a pathological ARMC5 or KDM1A variant, no genetic alterations were found. In patients for whom a germline pathological variant was known, we detected a somatic event in 56 of the 61 nodules sampled (92%).

Discussion: Our study is the first to explore the mutational profile of different nodules from the same patient isolated by macrodissection on a series of BMAD and the first to study this profile in patients with bi-allelic KDM1A inactivation. We confirm the heterogeneity of ARMC5 secondary events and show a high homogeneity of KDM1A alterations. In patients without germline alteration no somatic alterations were found suggesting that the molecular mechanisms in these patients remain to be discovered.

Volume 90

25th European Congress of Endocrinology

Istanbul, Turkey
13 May 2023 - 16 May 2023

European Society of Endocrinology 

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