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Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy

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Abstract

Molecular characterization of gastrointestinal stromal tumors (GISTs) plays an increasing role not only for the patient’s prognosis but also for treatment options and in the context of resistance to therapy. Several mutational subtypes in KIT or platelet-derived growth factor receptor-α (PDGFRα) have been identified to be correlated with a different clinical behavior of GISTs. In KIT exon 11, deletions in the proximal part are associated with a high metastatic risk, whereas duplications in the distal part lead to a less aggressive phenotype. GISTs of the small bowel with a duplication in KIT exon 9 are often high risk tumors. In contrast, PDGFRα exon 18 mutated GISTs tend to have a low malignant potential. The authors suggest to include these molecular data together with classical parameters such as mitotic count and tumor size into the risk assessment of GISTs. The first choice for treatment of GISTs is still the surgical resection. In advanced tumors, which cannot be R0 resected, the neoadjuvant treatment with the tyrosine kinase inhibitor imatinib is now well established. Furthermore, an adjuvant treatment of locally R0-resected intermediate and high risk tumors is evaluated in several international clinical trials. For metastatic disease, treatment with imatinib is still the first option, but with new upcoming substances, the molecular characterization of GISTs may become mandatory. Very recently, it has been shown that sunitinib may be especially effective in GISTs with KIT exon 9 mutation, whereas these tumors show only an intermediate response to imatinib. A European Organisation for Research and Treatment of Cancer clinical trial randomizing patients according to their mutational status is under preparation. Secondary resistance to imatinib treatment is increasing, at least partly due to secondary mutations in the tyrosine kinase domain of the KIT receptor. Once a lesion has been shown to carry such a mutation, the local excision may be useful, mean while still responding metastases are further controlled by continuing imatinib. Taken together, the molecular characterization of GISTs turns out to play a central role before and during the treatment with tyrosine kinase inhibitors, which have improved the treatment of GIST patients dramatically.

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Authors and Affiliations

  1. Department of Pathology, University of Bonn Medical School, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Eva Wardelmann, Reinhard Büttner, Sabine Merkelbach-Bruse & Hans-Ulrich Schildhaus

  2. Department of Pathology, University of Bonn Medical School, P.O. Box 2120, 53011, Bonn, Germany

    Eva Wardelmann

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  1. Eva Wardelmann
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Wardelmann, E., Büttner, R., Merkelbach-Bruse, S. et al. Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy. Virchows Arch 451, 743–749 (2007). https://doi.org/10.1007/s00428-007-0473-9

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