ECE2017 Guided Posters Neuroendocrinology & Growth Hormones (10 abstracts)
Somatic mutations in USP8 are frequent events in pituitary tumors causing Nelson’s syndrome
Luis G Perez-Rivas 1 , Marily Theodoropoulou 1, , Troy H Puar 3 , Julia Fazel 1 , Mareike R Stieg 2 , Francesco Ferraù 4 , Guillaume Assié 5 , Monica R Gadelha 6 , Timo Deutschbein 7 , Maria C Fragoso 8 , Benno Küsters 9 , Márta Korbonits 4 , Jérôme Bertherat 5 , Günter K Stalla 2 , Ad R Hermus 3 , Felix Beuschlein 1 & Martin Reincke 1
1Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany; 2Department of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany; 3Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands; 4Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 5Inserm Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Institut Cochin, Université Paris Descartes, Paris, France; 6Division of Endocrinology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 7Division of Endocrinology and Diabetology, Department of Internal Medicine, Universitätsklinikum Würzburg, University of Würzburg, Würzburg, Germany; 8Unidade de Neuroendocrinologia, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São P, São Paulo, Brazil; 9Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Recent studies have reported a high prevalence of USP8 mutations in corticotroph adenomas causing Cushing’s disease. Nelson’s syndrome is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory Cushing’s disease that is caused by the development of an ACTH-secreting tumor in the pituitary gland. Whether USP8 alterations are also present in Nelson’s tumors has not been studied in detail so far.
Methods: We have screened for mutations in the exon 14 of USP8 in tumors from 32 patients who were diagnosed with Nelson’s syndrome (28 females, four males). Genomic DNA was extracted from fresh-frozen or FFPE adenomas. The presence of mutations was analyzed by Sanger sequencing. Mutational status was correlated to clinical data.
Results: In our cohort, 15/32 tumors presented a mutation in the exon 14 of USP8, a prevalence similar to that reported in Cushing’s disease, with c.2159C>A (p.Pro720Gln) being the most frequent (8/32), followed by c.2155_2157delTCC (p.Ser718del, 4/32) and c.2152T>C (p.Ser718Pro, 3/32). Two USP8 WT cases were categorized as atypical pituitary tumors and excluded from subsequent analyses. Mutations were found exclusively in females (15/27, 55%; vs 0/3 males). Other variables, such as age at diagnosis of Nelson’s syndrome, BMI, hyperpigmentation, visual field defects, adenoma size or mortality did not significantly differ between patients with WT and mutant tumors. Regarding the hormonal status, patients with mutant tumors tended to exhibit higher levels of plasma ACTH at time of Nelson’s diagnosis (median WT 1335 pg/ml vs mutant 1668 pg/ml; P=0.098; n=25) and significant changes after surgery (median 131 vs 639, P=0.043; n=22). Postoperative normalization of plasma ACTH was reached more frequently in patients with WT tumors (4/12, 33% vs 1/10, 10%) but without statistical significance (P=0.323). No differences were observed in tumor control after surgery.
Conclusion: Somatic mutations in the USP8 gene are common in Nelson’s syndrome and may be related to a more severe hormonal phenotype.
Volume 49
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Endocrine Abstracts
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