Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4

Authors

  • Waki Hosoda,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Peter Chianchiano,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • James F. Griffin,

    1. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Meredith E. Pittman,

    1. Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
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  • Lodewijk A. A. Brosens,

    1. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Michaël Noë,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Jun Yu,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Koji Shindo,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Masaya Suenaga,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Neda Rezaee,

    1. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Raluca Yonescu,

    1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Yi Ning,

    1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Jorge Albores-Saavedra,

    1. Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico
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  • Naohiko Yoshizawa,

    1. The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
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  • Kenichi Harada,

    1. Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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  • Akihiko Yoshizawa,

    1. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
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  • Keiji Hanada,

    1. Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan
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  • Shuji Yonehara,

    1. Department of Pathology, Onomichi General Hospital, Onomich, Japan
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  • Michio Shimizu,

    1. Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan
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  • Takeshi Uehara,

    1. Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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  • Jaswinder S Samra,

    1. Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia
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  • Anthony J. Gill,

    1. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia
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  • Christopher L. Wolfgang,

    1. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Michael G. Goggins,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    3. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Ralph H. Hruban,

    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Laura D. Wood

    Corresponding author
    1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Correspondence to: Laura D. Wood, Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, CRB2 Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA. e-mail: ldwood@jhmi.edu

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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 10 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.

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