{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:25:18Z","timestamp":1793157918604,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2019\/35\/N\/NZ5\/03121"],"award-info":[{"award-number":["2019\/35\/N\/NZ5\/03121"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing\u2019s disease (CD), however, some remain clinically silent. Recurrent <jats:italic>USP8<\/jats:italic>, <jats:italic>USP48<\/jats:italic>, <jats:italic>BRAF<\/jats:italic> and <jats:italic>TP53<\/jats:italic> mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in <jats:italic>USP8<\/jats:italic>, <jats:italic>USP48<\/jats:italic> and <jats:italic>BRAF<\/jats:italic> with Sanger sequencing, while 128 of these patients were screened for <jats:italic>TP53<\/jats:italic> mutations with next generation sequencing and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>USP8<\/jats:italic> mutations were found in 41% CD and 8,5% silent tumors, while <jats:italic>USP48<\/jats:italic> mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No <jats:italic>BRAF<\/jats:italic> mutations were found. Four <jats:italic>TP53<\/jats:italic> mutations were identified (2 in CD, 2 in silent tumors) in tumors with size &amp;gt;10mm including 3 invasive ones. They were found in Crooke\u2019s cell and sparsely granulated tumors. Tumors with missense <jats:italic>TP53<\/jats:italic> mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift <jats:italic>TP53<\/jats:italic> variant had low protein expression. <jats:italic>TP53<\/jats:italic> mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We confirmed high prevalence of <jats:italic>USP8<\/jats:italic> mutations and low incidence of <jats:italic>USP48<\/jats:italic> and <jats:italic>TP53<\/jats:italic> mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. <jats:italic>TP53<\/jats:italic> mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1302667","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:13:35Z","timestamp":1709183615000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors"],"prefix":"10.3389","volume":"15","author":[{"given":"Monika","family":"P\u0119kul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Szczepaniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Kober","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Rusetska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata J.","family":"Mossakowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon","family":"Baluszek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Kowalik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Maksymowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grzegorz","family":"Zieli\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Kunicki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemys\u0142aw","family":"Witek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Bujko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11102-018-0864-8","article-title":"Silent corticotroph adenomas","volume":"21","author":"Ben-Shlomo","year":"2018","journal-title":"Pituitary"},{"key":"B2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.17925\/EE.2019.15.1.30","article-title":"Functioning pituitary adenomas - Current treatment options and emerging medical therapies","volume":"15","author":"Varlamov","year":"2019","journal-title":"Eur Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/cen.13457","article-title":"Genetics of Cushing\u2019s disease","volume":"88","author":"Albani","year":"2018","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3166","article-title":"Mutations in the deubiquitinase gene USP8 cause Cushing\u2019s disease","volume":"47","author":"Reincke","year":"2015","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.20","article-title":"Recurrent gain-of-function USP8 mutations in Cushing\u2019s disease","volume":"25","author":"Ma","year":"2015","journal-title":"Cell Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"E997","DOI":"10.1210\/jc.2015-1453","article-title":"The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing\u2019s disease","volume":"100","author":"Perez-Rivas","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noz109","article-title":"Driver mutations in USP8 wild-type Cushing\u2019s disease","volume":"21","author":"Sbiera","year":"2019","journal-title":"Neuro Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-018-05275-5","article-title":"Identification of recurrent USP48 and BRAF mutations in Cushing\u2019s disease","volume":"9","author":"Chen","year":"2018","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-19-0194","article-title":"USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status","volume":"181","author":"Bujko","year":"2019","journal-title":". 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