title: Fhit down-regulation is an early event in pancreatic carcinogenesis.
abstract: Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC.
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. matteo.fassan@unipd.it.|Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Gabelli 61, 35121, Padua, Italy. matteo.fassan@unipd.it.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0001-6515-5482
authors.initials: M
authors.lastname: Fassan
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
authors.forename: Borislav
authors.initials: B
authors.lastname: Rusev
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.affiliation: Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.|Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy.|Department of Pathology, Santa Chiara Hospital, Trento, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchini
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mafficini
authors.affiliation: Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Paiella
authors.affiliation: Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvia
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cataldo
authors.affiliation: ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.|Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D002278:Carcinoma in Situ / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase
keywords: Biomarkers; Carcinogenesis; FHIT; Pancreatic cancer