Luis G Pérez-Rivas1, Marily Theodoropoulou1,2, Troy H Puar3,4, Julia Fazel1, Mareike R Stieg2, Francesco Ferraù5, Guillaume Assié6, Monica R Gadelha7, Timo Deutschbein8, Maria C Fragoso9, Benno Kusters10, Wolfgang Saeger11, Jürgen Honegger12, Michael Buchfelder13, Márta Korbonits5, Jérôme Bertherat6, Günter K Stalla2, Ad R Hermus3, Felix Beuschlein1,14, Martin Reincke1. 1. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany. 2. Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany. 3. Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands. 4. Department of Endocrinology, Changi General Hospital, Singapore, Singapore. 5. Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 6. Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris; Inserm Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Institut Cochin, Université Paris Descartes, Paris, France. 7. Division of Endocrinology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 8. Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital Würzburg, University of Würzburg, Würzburg, Germany. 9. Unidade 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 Paulo, São Paulo, Brasil. 10. Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands. 11. Institut für Neuropathologie der Universität Hamburg, Hamburg, Germany. 12. Department of Neurosurgery, Eberhard Karls University Tübingen, Tübingen, Germany. 13. Neurochirurgische Klinik, Klinikum der Universität Erlangen, Erlangen, Germany. 14. Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland.
Abstract
OBJECTIVE: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson's tumors has not been studied in detail so far. DESIGN AND METHODS: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. RESULTS: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor. CONCLUSION: Somatic mutations in USP8 are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.
OBJECTIVE: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson's tumors has not been studied in detail so far. DESIGN AND METHODS: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. RESULTS: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor. CONCLUSION: Somatic mutations in USP8 are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.
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