Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorPEREZ-RIVAS, Luis G.
dc.contributor.authorTHEODOROPOULOU, Marily
dc.contributor.authorPUAR, Troy H.
dc.contributor.authorFAZEL, Julia
dc.contributor.authorSTIEG, Mareike R.
dc.contributor.authorFERRAU, Francesco
dc.contributor.authorASSIE, Guillaume
dc.contributor.authorGADELHA, Monica R.
dc.contributor.authorDEUTSCHBEIN, Timo
dc.contributor.authorFRAGOSO, Maria C.
dc.contributor.authorKUSTERS, Benno
dc.contributor.authorSAEGER, Wolfgang
dc.contributor.authorHONEGGER, Juergen
dc.contributor.authorBUCHFELDER, Michael
dc.contributor.authorKORBONITS, Marta
dc.contributor.authorBERTHERAT, Jerome
dc.contributor.authorSTALLA, Guenter K.
dc.contributor.authorHERMUS, Ad R.
dc.contributor.authorBEUSCHLEIN, Felix
dc.contributor.authorREINCKE, Martin
dc.date.accessioned2018-02-02T16:58:24Z
dc.date.available2018-02-02T16:58:24Z
dc.date.issued2018
dc.description.abstractObjective: 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.
dc.description.indexMEDLINE
dc.description.sponsorshipElse Kroner-Fresenius-Stiftung [2012 A103, 2015_A228]
dc.description.sponsorshipDeutsche Forschungsgemeinschaft [CRC/Transregio 205/1]
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG) [RE 752/20-1]
dc.description.sponsorshipInterdisciplinary Center for Clinical Research (IZKF) of the University of Wurzburg [Z-2/57]
dc.description.sponsorshipPeople Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7) under REA grant [608 765]
dc.description.sponsorshipMedical Research Grant, UK
dc.description.sponsorshipPfizer
dc.identifier.citationEUROPEAN JOURNAL OF ENDOCRINOLOGY, v.178, n.1, p.57-63, 2018
dc.identifier.doi10.1530/EJE-17-0634
dc.identifier.eissn1479-683X
dc.identifier.issn0804-4643
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/24944
dc.language.isoeng
dc.publisherBIOSCIENTIFICA LTD
dc.relation.ispartofEuropean Journal of Endocrinology
dc.rightsrestrictedAccess
dc.rights.holderCopyright BIOSCIENTIFICA LTD
dc.subject.othersporadic pituitary-adenomas
dc.subject.otherprotein gene-mutations
dc.subject.othergermline aip mutations
dc.subject.othercushings-disease
dc.subject.othertranssphenoidal surgery
dc.subject.otherbilateral adrenalectomy
dc.subject.otheracth
dc.subject.otherpatient
dc.subject.othercohort
dc.subject.otherreappraisal
dc.subject.wosEndocrinology & Metabolism
dc.titleSomatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson's tumor
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countrySuíça
hcfmusp.affiliation.countryHolanda
hcfmusp.affiliation.countryFrança
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countrySingapura
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryisode
hcfmusp.affiliation.countryisosg
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisofr
hcfmusp.affiliation.countryisonl
hcfmusp.affiliation.countryisoch
hcfmusp.author.externalPEREZ-RIVAS, Luis G.:Ludwig Maximilians Univ Munchen, Med Klin, Munich, Germany; Ludwig Maximilians Univ Munchen, Poliklin 4, Munich, Germany
hcfmusp.author.externalTHEODOROPOULOU, Marily:Ludwig Maximilians Univ Munchen, Med Klin, Munich, Germany; Ludwig Maximilians Univ Munchen, Poliklin 4, Munich, Germany; Max Planck Inst Psychiat, Clin Neuroendocrinol, Munich, Germany
hcfmusp.author.externalPUAR, Troy H.:Radboud Univ Nijmegen, Div Endocrinol, Dept Internal Med, Med Ctr, Nijmegen, Netherlands; Changi Gen Hosp, Dept Endocrinol, Singapore, Singapore
hcfmusp.author.externalFAZEL, Julia:Ludwig Maximilians Univ Munchen, Med Klin, Munich, Germany; Ludwig Maximilians Univ Munchen, Poliklin 4, Munich, Germany
hcfmusp.author.externalSTIEG, Mareike R.:Max Planck Inst Psychiat, Clin Neuroendocrinol, Munich, Germany
hcfmusp.author.externalFERRAU, Francesco:Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Ctr Endocrinol, London, England
hcfmusp.author.externalASSIE, Guillaume:Cochin Hosp, AP HP, Dept Endocrinol, Paris, France; Univ Paris 05, Inst Cochin, CNRS, INSERM,Unite 1016,Unite Mixte Rech, Paris, France
hcfmusp.author.externalGADELHA, Monica R.:Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Div Endocrinol, Rio De Janeiro, Brazil
hcfmusp.author.externalDEUTSCHBEIN, Timo:Univ Wurzburg, Univ Hosp Wurzburg, Div Endocrinol & Diabetol, Dept Internal Med, Wurzburg, Germany
hcfmusp.author.externalKUSTERS, Benno:Radboud Univ Nijmegen, Dept Pathol, Med Ctr, Nijmegen, Netherlands
hcfmusp.author.externalSAEGER, Wolfgang:Univ Hamburg, Inst Neuropathol, Hamburg, Germany
hcfmusp.author.externalHONEGGER, Juergen:Eberhard Karls Univ Tubingen, Dept Neurosurg, Tubingen, Germany
hcfmusp.author.externalBUCHFELDER, Michael:Klinikum Univ Erlangen, Neurochirurg Klin, Erlangen, Germany
hcfmusp.author.externalKORBONITS, Marta:Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Ctr Endocrinol, London, England
hcfmusp.author.externalBERTHERAT, Jerome:Cochin Hosp, AP HP, Dept Endocrinol, Paris, France; Univ Paris 05, Inst Cochin, CNRS, INSERM,Unite 1016,Unite Mixte Rech, Paris, France
hcfmusp.author.externalSTALLA, Guenter K.:Max Planck Inst Psychiat, Clin Neuroendocrinol, Munich, Germany
hcfmusp.author.externalHERMUS, Ad R.:Radboud Univ Nijmegen, Div Endocrinol, Dept Internal Med, Med Ctr, Nijmegen, Netherlands
hcfmusp.author.externalBEUSCHLEIN, Felix:Ludwig Maximilians Univ Munchen, Med Klin, Munich, Germany; Ludwig Maximilians Univ Munchen, Poliklin 4, Munich, Germany; Univ Zurich, Klin Endokrinol Diabetol & Klin Ernahrung, Zurich, Switzerland
hcfmusp.author.externalREINCKE, Martin:Ludwig Maximilians Univ Munchen, Med Klin, Munich, Germany; Ludwig Maximilians Univ Munchen, Poliklin 4, Munich, Germany
hcfmusp.citation.scopus41
hcfmusp.contributor.author-fmusphcMARIA CANDIDA BARISSON VILLARES FRAGOSO
hcfmusp.description.beginpage57
hcfmusp.description.endpage63
hcfmusp.description.issue1
hcfmusp.description.volume178
hcfmusp.origemWOS
hcfmusp.origem.pubmed28982703
hcfmusp.origem.scopus2-s2.0-85037712814
hcfmusp.origem.wosWOS:000419119500011
hcfmusp.publisher.cityBRISTOL
hcfmusp.publisher.countryENGLAND
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