Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis

Authors

  • Gabriella Arne,

    1. Lundberg Laboratory for Cancer Research, Department of Pathology, Sahlgrenska Academy at The University of Gothenburg, Göteborg, Sweden
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  • Erik Kristiansson,

    1. Department of Neuroscience and Physiology, Sahlgrenska Academy at The University of Gothenburg, Göteborg, Sweden
    2. Mathematical Statistics, Chalmers University of Technology, Göteborg, Sweden
    3. Mathematical Statistics, University of Gothenburg, Göteborg, Sweden
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  • Olle Nerman,

    1. Mathematical Statistics, Chalmers University of Technology, Göteborg, Sweden
    2. Mathematical Statistics, University of Gothenburg, Göteborg, Sweden
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  • Lars-Gunnar Kindblom,

    1. Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital, Birmingham, United Kingdom
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  • Håkan Ahlman,

    1. Department of Surgery, Sahlgrenska Academy at The University of Gothenburg, Göteborg, Sweden
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  • Bengt Nilsson,

    1. Department of Surgery, Sahlgrenska Academy at The University of Gothenburg, Göteborg, Sweden
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  • Ola Nilsson

    Corresponding author
    1. Lundberg Laboratory for Cancer Research, Department of Pathology, Sahlgrenska Academy at The University of Gothenburg, Göteborg, Sweden
    • Lundberg Laboratory for Cancer Research, Department of Pathology, Sahlgrenska University Hospital, Gula Stråket 8, 413 45 Göteborg, Sweden
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    • Tel.: +46-73-9011090, Fax: +46-31-417283


Abstract

In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on nine tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by meta-analysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n = 180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, platelet-derived growth factor receptor α (PDGFRA), or wild-type tumors (0–17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio = 2.23, p = 0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, National Institutes of Health (NIH) risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis.

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