Germline targeted next-generation sequencing in patients with adrenal incidentalomas

Erika Messina; Soraya Puglisi; Maria Scatolini; Pasquale Tomaiuolo; Anja Barač Nekić; Valentina Morelli; Ylenia Alessi; Karin Zibar Tomsic; Serena Palmieri; Francesco Ferrau; Enrico Grosso; Anna Pia; Giuseppe Reimondo; Iacopo Chiodini; Darko Kastelan; Massimo Terzolo

doi:10.1530/endoabs.99.P417

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Endocrine Abstracts (2024) 99 P417 | DOI: 10.1530/endoabs.99.P417

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

Germline targeted next-generation sequencing in patients with adrenal incidentalomas

Erika Messina ¹ , Soraya Puglisi ¹ , Maria Scatolini ² , Pasquale Tomaiuolo ² , Anja Barač Nekić ³ , Valentina Morelli ⁴ , Ylenia Alessi ⁵ , Karin Zibar Tomsic ³ , Serena Palmieri ⁶ , Francesco Ferraù ⁵ , Enrico Grosso ² , Anna Pia ¹ , Giuseppe Reimondo ¹ , Iacopo Chiodini ⁷ , Darko Kastelan ³ & Massimo Terzolo ¹

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¹Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Italy; ²Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, Ponderano, Italy; ³Department of Endocrinology, University Hospital Zagreb, Zagreb, Italy; ⁴Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy; ⁵Department of Human Pathology G. Barresi, Endocrine Unit, University Hospital G. Martino, University of Messina, Messina, Italy; ⁶Unit of Endocrinology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy; ⁷Department of Biotechnology and Translational Medicine, Unit of Endocrinology, Ospedale Niguarda Cà Granda, University of Milan, Milan, Italy

Background: The advances in next-generation sequencing (NGS) technologies and bioinformatic analysis have shed light on genetic alterations, either of germline or somatic origin, in many disorders, including adrenocortical diseases. However, our knowledge on genomic characteristics in benign adrenal tumors of serendipitous discovery (adrenal incidentalomas) remain scarce.The aim of this study was to understand the pathogenic role of germline variants in adrenal incidentalomas.

Methods: To identify disease-causing variants, in this multicenter study we performed targeted NGS of 191 patients with adrenal incidentalomas, using a custom panel of 21 genes potentially involved in the pathogenesis of adrenal tumors. Pathogenicity role of germline variants (GV) was assessed using ClinVar database or, in absence, using ACMG guidelines throw VarSome tool. Clinical and hormonal data were collected at diagnosis and at last follow-up visit. The median follow-up was 8.5 years (IQR 3–15 years).

Results: NGS analysis in 10 patients (5.2%) identified GV located in the following genes: ARMC5 (n=3), APC (n=1), CACNA1H (n=2), ZNRF3 (n=2), PDE11A (n=1), GNAS (n=1). We found two likely-pathogenic variants (LP) in ZNRF3 and GNAS genes and eight variants of suspicious pathogenicity (VUS/LP) in ARMC5, APC, CACNA11H, ZNRF3 and PDE11A genes. Two of the three patients with GV in ARMC5 gene had bilateral lesions at diagnosis and one of these developed hypertension during the follow-up despite the absence of cortisol autonomy. The patient with GV in APC gene did not present associated colon polyposis, significant changes of tumor characteristics and related comorbidities over time. None of the patients with GV in CACNA1H gene showed alterations in the aldosterone-renin ratio, whereas one was diagnosed with mild autonomous cortisol secretion and underwent adrenalectomy. Both patients with GV in ZNRF3 gene had unilateral adrenal lesions that did not changed their characteristics and developed hypertension during follow-up, despite the absence of mineralocorticoid and glucocorticoid excess. The patient with GV in PDE11A gene presented with unilateral lesions and hypertension, without significant changes of tumor characteristics and related comorbidities over time. A similar behavior was observed in the patient with a GV in GNAS gene (unilateral tumor, no significant radiological changes with time), who developed hypertension during follow-up.

Conclusion: GV with a pathogenic or potential pathogenic role were found in 5.2% of patients with benign adrenal incidentalomas. The small number of cases hampered the identification of a clear genotype-phenotype correlation; however, these data provide new insights for a better characterization of benign adrenal incidentalomas.