title: PBRM1 loss is a late event during the development of cholangiocarcinoma.
abstract: OBJECTIVE
  Somatic mutations in genes encoding chromatin remodellers have been reported recently in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodellers in cholangiocarcinoma is the Polybromo-1 (PBRM1) gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. The aim of this study was to determine the timing of PBRM1 mutations in biliary carcinogenesis.
  
  
  RESULTS
  In order to accomplish this goal, we used immunohistochemistry to assess PBRM1 protein expression in a series of precursor lesions and invasive biliary carcinomas. Previous studies have correlated loss of protein expression on immunohistochemistry with inactivating mutations in this tumour suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intra-epithelial neoplasia (BilIN) specimens, including 25 intrahepatic BilINs and 19 gallbladder BilINs.
  
  
  CONCLUSIONS
  These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodelling genes in carcinogenesis.
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.|Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Claudio
authors.identifier: http://orcid.org/0000-0003-4901-4908
authors.initials: C
authors.lastname: Luchini
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Robertson
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Felsenstein
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Surgery, University and Hospital Trust of Verona, Verona, Italy.|Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pea
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Nottegar
authors.affiliation: National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy.|Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Veronese
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.affiliation: Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.|ARC-Net Research Center, University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Laura D
authors.identifier: http://orcid.org/0000-0003-3096-652X
authors.initials: LD
authors.lastname: Wood
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000401:mortality; D004268:DNA-Binding Proteins; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors
keywords: BilIN; PBRM1; biliary dysplasia; cholangiocarcinoma; chromatin remodelling