Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening

Authors

  • Fátima Carneiro,

    Corresponding author
    1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
    2. Medical Faculty of the University of Porto/HS João, Porto, Portugal
    • IPATIMUP, Rua Dr Roberto Frias S/N, 4200-465 Porto, Portugal.
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    • The authors wish it to be known that FC and DGH should be regarded as joint first authors

  • David G Huntsman,

    Corresponding author
    1. British Columbia Cancer Agency, Vancouver, Canada
    2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
    • Department of Pathology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada, V5Z 4E6.
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    • The authors wish it to be known that FC and DGH should be regarded as joint first authors

  • Thomas C Smyrk,

    1. Department of Pathology, Mayo Clinic, Rochester, Minnesota, USA
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  • David A Owen,

    1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
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  • Raquel Seruca,

    1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
    2. Medical Faculty of the University of Porto/HS João, Porto, Portugal
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  • Paul Pharoah,

    1. Cancer Research UK Department of Oncology and Strangeways Research Laboratory, Cambridge, UK
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  • Carlos Caldas,

    1. Department of Oncology, University of Cambridge and Hutchison/MRC Research Centre, Addenbrooke's Hospital, Cambridge, UK
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  • Manuel Sobrinho-Simões

    1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
    2. Medical Faculty of the University of Porto/HS João, Porto, Portugal
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Abstract

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome caused, in 30–40% of cases, by germline mutations of the E-cadherin/CDH1 gene. The presence of clinically undetectable early gastric cancers has been previously reported in ten of ten prophylactic gastrectomies from germline E-cadherin mutation carriers. In the present study, detailed maps of the distribution of invasive cancers in nine of these ten stomachs were produced and precursor lesions of HDGC searched for. The nine gastrectomy specimens contained from 1 to 161 foci of early diffuse gastric cancer, occupying 0.005–2.96% of the gastric mucosa. Seven specimens contained focal in situ signet ring carcinoma. Pagetoid spread of signet ring cells was observed beneath the epithelial lining of gastric foveolae/glands. Helicobacter pylori organisms and associated pathology were absent from all cases. Two-dimensional maps of the gastrectomy specimens revealed lesions throughout the gastric mucosa without evidence of antral clustering. The distribution and size of the cancers in the gastrectomy specimens indicate that standard endoscopic screening with random or geographically targeted biopsies is unlikely to provide sufficiently sensitive clinical screening for at-risk individuals. An in situ precursor of signet ring carcinoma was identified and a model for neoplastic progression in the setting of HDGC is proposed. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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