Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Gastrointestinal Stromal Tumors (GIST) [C16.-, C17.-, C18.-, C19, C21.-]

OMIM numbers: 606764164920 (KIT), 173490 (PDGFRa)

Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak

Scientific Background

GISTs are the most frequent mesenchymal neoplasms of the gastrointestinal tract. They represent a morphological and biological continuum from coincidentally discovered benign lumps < 10 mm in size to large sarcomas. There are 3 morphologic subgroups of GISTs: approx. 70% are spindle-shaped, approx. 10% are of the epithelioid and another 20% of the mixed spindle/epithelioid subtype. Immunohistochemistry is crucial for a diagnosis, as GISTs can easily be mixed up with neuroendocrine, neurogenic or epithelial tumors. In approximately 95% of all GISTs, antibodies againstCD117 (KIT receptor) can be detected. Moreover, approximately 70-80% of all cases express the stem cell antigen CD34 and the vast majority of all cases the marker DOG1.

Despite their clinicopathological difference, most GISTs share the same genetic profile. It includes KIT and platelet-derived growth factor receptor-alpha (PDGFRA) gain-of-function mutations. Both genes encode for receptor tyrosine kinases that activate different signaling pathways after binding of a ligand and therefore govern important cell functions such as cell proliferation or apoptosis. Mutations in KIT cause a constitutive activation of the tyrosine kinase, which can already be detected in small tumors with a diameter of < 1 cm and which makes it an early pathogenetic event. Due to its relevance regarding the prognostic significance as well as the prediction on the response to treatment, a mutational analysis should be carried out once the diagnosis has been established.


Analysis of KIT: The frequency of KIT mutations is approximately 80-90%. Imatinib mesylate (Gleevec/Glivec) is a tyrosine kinase inhibitor (TKI) that specifically inhibits ABL, KIT and PDGFRα receptor tyrosine kinases by competing with ATP for the binding in the tyrosine kinase pocket of the receptor and therefore deactivates downstream signaling pathways. While most patients benefit from such a treatment, resistance may occur due to secondary KIT or PDGFRA mutations. Therefore 2 categories of KIT or PDGFRA mutations are distinguished: mutations that are diagnosed in the primary tumor prior to treatment with a TKI and mutations that are detected during treatment with a TKI and that cause resistance. The most frequent mutations in KIT are found in exon 11 and are very heterogeneous regarding length and type (deletions, insertions, point mutations and combinations). The significance of the various types of mutations in exon 11 regarding the prognosis of a GIST is assessed differently by experts. Furthermore, there is no significant correlation to the morphology of a tumor. However, tumors with exon 11 mutations respond to a treatment with imatinib in > 80% of all cases. In 10-15% of all cases, KIT mutations are found in exon 9. The mutation which almost always occurs is a 6 base pair insertion, which leads to the duplication of the amino acids alanine 502 and tyrosine 503. Exon 9 mutations predominantly occur in GISTs with localization in the small intestine. Only about half of them respond to imatinib. It was shown, however, that these patients benefited from taking 800 mg Glivec/day instead of 400 mg Glicec/day right from the start or from being treated with another TKI (sunitinib). KIT mutations in exon 13 (Lys642Glu) and exon 17 (Asn822Lys) are rare. A primary resistance can be expected in the case of the exon 17 mutation.