{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:08:16Z","timestamp":1791648496938,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008359","name":"Maag Lever Darm Stichting","doi-asserted-by":"publisher","award":["CDG 16\u201013"],"award-info":[{"award-number":["CDG 16\u201013"]}],"id":[{"id":"10.13039\/501100008359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Carcinogenesis of primary sclerosing cholangitis (PSC)\u2010associated cholangiocarcinoma (CCA) is largely unexplored. Improved understanding of the molecular events involved may guide development of novel avenues for rational clinical management. We aimed to assess the genetic alterations during progression of the neoplastic cascade from biliary dysplasia towards CCA in PSC. Forty\u2010four resection specimens or biopsies of PSC patients with biliary dysplasia (<jats:italic>n<\/jats:italic>\u2009=\u20092) and\/or CCA (<jats:italic>n<\/jats:italic>\u2009=\u200942) were included. DNA was extracted from sections of formalin\u2010fixed paraffin\u2010embedded tissue blocks with dysplasia (<jats:italic>n<\/jats:italic>\u2009=\u200923), CCA (<jats:italic>n<\/jats:italic>\u2009=\u200969), and nonneoplastic tissue (<jats:italic>n<\/jats:italic>\u2009=\u200928). A custom\u2010made next\u2010generation sequencing (NGS) panel of 28 genes was used for mutation and copy number variation (CNV) detection. In addition, CNVs of <jats:italic>CDKN2A<\/jats:italic>, <jats:italic>EGFR<\/jats:italic>, <jats:italic>MCL1<\/jats:italic>, and <jats:italic>MYC<\/jats:italic> were examined by fluorescence <jats:italic>in situ<\/jats:italic> hybridization. Alterations in 16 low\u2010grade dysplasia samples included loss of <jats:italic>FGFR1<\/jats:italic> (19%), <jats:italic>CDKN2A<\/jats:italic> (13%), and <jats:italic>SMAD4<\/jats:italic> (6%), amplification of <jats:italic>FGFR3<\/jats:italic> (6%), <jats:italic>EGFR<\/jats:italic> (6%), and <jats:italic>ERBB2<\/jats:italic> (6%), and mutations in <jats:italic>SMAD4<\/jats:italic> (13%). High\u2010grade dysplasia (<jats:italic>n<\/jats:italic>\u2009=\u20097) is characterized by <jats:italic>MYC<\/jats:italic> amplification (43%), and mutations in <jats:italic>ERBB2<\/jats:italic> (71%) and <jats:italic>TP53<\/jats:italic> (86%). <jats:italic>TP53<\/jats:italic> mutations are the most common aberrations in PSC\u2010CCA (30%), whereas mutations in <jats:italic>KRAS<\/jats:italic> (16%), <jats:italic>GNAS<\/jats:italic> (14%), and <jats:italic>PIK3CA<\/jats:italic> (9%) are also common. In conclusion, PSC\u2010CCA exhibits a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early, whereas mutations in <jats:italic>ERBB2<\/jats:italic>, <jats:italic>TP53<\/jats:italic>, and <jats:italic>KRAS<\/jats:italic> appear later in the development of CCA. These findings are promising for the development of NGS\u2010guided diagnostic strategies in PSC\u2010CCA. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5994","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:45Z","timestamp":1658966445000},"page":"227-235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis"],"prefix":"10.1002","volume":"258","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5410-9878","authenticated-orcid":false,"given":"Eline JCA","family":"Kamp","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winand NM","family":"Dinjens","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Doukas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"van Marion","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Verheij","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC University Medical Center Amsterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyriel Y","family":"Ponsioen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam UMC University Medical Center Amsterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco J","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas","family":"Groot Koerkamp","sequence":"additional","affiliation":[{"name":"Department of Surgery, Erasmus MC University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palak J","family":"Trivedi","sequence":"additional","affiliation":[{"name":"National Institute for Health Research 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