Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer

Authors

  • Kirsten D. Mertz,

    1. Department of Pathology, Brigham and Women's Hospital, Boston, MA
    2. Harvard Medical School, Boston, MA
    Current affiliation:
    1. Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
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  • Francesca Demichelis,

    1. Department of Pathology, Brigham and Women's Hospital, Boston, MA
    2. Harvard Medical School, Boston, MA
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  • Andrea Sboner,

    1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
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  • Michelle S. Hirsch,

    1. Department of Pathology, Brigham and Women's Hospital, Boston, MA
    2. Harvard Medical School, Boston, MA
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  • Paola Dal Cin,

    1. Department of Pathology, Brigham and Women's Hospital, Boston, MA
    2. Harvard Medical School, Boston, MA
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  • Kirsten Struckmann,

    1. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Martina Storz,

    1. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Simone Scherrer,

    1. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Daniel M. Schmid,

    1. Department of Urology, University Hospital Zurich, Zurich, Switzerland
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  • Räto T. Strebel,

    1. Department of Urology, University Hospital Zurich, Zurich, Switzerland
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  • Nicole M. Probst-Hensch,

    1. Molecular Epidemiology, Institute of Social and Preventive Medicine, University Hospital Zurich, Zurich, Switzerland
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  • Mark Gerstein,

    1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
    2. Department of Computer Science, Yale University, New Haven, CT
    3. Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT
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  • Holger Moch,

    1. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Mark A. Rubin

    Corresponding author
    1. Department of Pathology, Brigham and Women's Hospital, Boston, MA
    2. Harvard Medical School, Boston, MA
    3. Dana Farber Cancer Institute, Boston, MA
    4. Broad Institute of MIT and Harvard Medical School, Cambridge, MA
    • Department of Pathology and Laboratory Medicine, 1300 York Avenue, Room C 410-A (or Box #69), New York, NY 10021, USA

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    • Fax: +212-746-8816.


Abstract

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long-term follow-up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E-cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1-MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome. © 2008 Wiley-Liss, Inc.

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