Deletion of Trp‐557 and Lys‐558 in the juxtamembrane domain of the c‐kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors

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Abstract
Gastrointestinal stromal tumors (GISTs) typically express high levels of the Kit‐receptor. The majority of GISTs carry mutations in the c‐kit protooncogene clustering in exon 11. The significance of c‐kit mutations for the biological behavior of GISTs is still under discussion. We evaluated 55 sporadic GISTs with available follow‐up data for c‐kit mutations in the juxtamembrane domain and detected mutations in 35 cases (63.6%). We found a mutational hotspot in codons 557 (tryptophan) and 558 (lysine) preferentially in histomorphologically malignant tumors. In the group of GISTs carrying c‐kit mutations, 16 of 21 malignant, but only 3 of 8 benign GISTs and 3 of 6 lesions with uncertain malignant potential, carried mutations of Trp‐557 and/or Lys‐558. We investigated whether mutations in these 2 amino acids had an impact on biological behavior. Trp‐557 and/or Lys‐558 were mutated in all 15 metastatic GISTs carrying c‐kit mutations but only in a minority of nonmetastatic tumors. A combined deletion of Trp‐557 and Lys‐558 occurred exclusively in 8 metastatic GISTs. We conclude that in addition to histomorphological evaluation determination of mutations in exon 11 may be an additional parameter for predicting the metastatic risk of GISTs and may be important for the decision that patients will need close clinical follow‐up or further adjuvant treatment with kit antagonists.