title: Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.
abstract: High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Waki
authors.identifier: http://orcid.org/0000-0002-3288-8409
authors.initials: W
authors.lastname: Hosoda
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chianchiano
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Griffin
authors.affiliation: Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Pittman
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lodewijk Aa
authors.initials: LA
authors.lastname: Brosens
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michaël
authors.initials: M
authors.lastname: Noë
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Shindo
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Rezaee
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Raluca
authors.initials: R
authors.lastname: Yonescu
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Albores-Saavedra
authors.affiliation: The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Yoshizawa
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshizawa
authors.affiliation: Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hanada
authors.affiliation: Department of Pathology, Onomichi General Hospital, Onomich, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Yonehara
authors.affiliation: Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia.
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Goggins
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53 / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53
keywords: HG-PanIN; SMAD4; TP53; cancerization; pancreas; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; targeted next-generation sequencing; whole-exome sequencing