GIST SymposiumBiology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations*
Section snippets
KIT activation: A central tumorigenic event in GISTs
Many GISTs express constitutively activated KIT oncoproteins. The oncogenic activation of these KIT proteins does not depend on binding of KIT ligand; rather, KIT oncoproteins in GISTs often have structural changes which favor receptor oligomerization and cross-phosphorylation, even in the absence of ligand binding (Fig 3).13, 14, 15
Mechanisms of KIT regulation and dysregulation
As is the case with most RTKs, KIT kinase activity has multiple levels of control. Disruption of any of several control mechanisms may lead to aberrant kinase activation and oncogenesis. KIT kinase activity is controlled first and foremost by developmentally specific expression of the KIT protein. (If there is no protein expression, then there is no kinase activity). In the absence of ligand, normal KIT exists as a monomer in which enzymatic activity is inhibited by intrinsic structural
Biological consequences of KIT activation in GISTs
KIT activation normally occurs when the receptor is bound by its cognate ligand, stem-cell factor. Ligand-mediated KIT activation triggers various cell-signaling cascades that regulate cell behavior.45, 46 Examples of critical downstream signaling mechanisms include activation of cell survival (antiapoptotic) proteins, such as AKT, and cell proliferation–related proteins, such as MAPK p42/p44.45, 46 An intriguing aspect of KIT oncoproteins in hematologic neoplasms is that the exact signaling
Alternate KIT activation mechanisms in GISTs
KIT signaling pathways are activated in virtually all GISTs, and most GISTs have oncogenic mutations within the coding sequence of the KIT gene. However, even those tumors that lack such mutations can have biochemical features of high-level KIT kinase activation.15 As discussed later, KIT might be activated oncogenically by several alternate, nonmutational mechanisms, but to our knowledge, none of these mechanisms has been tested rigorously. It is important to consider alternative (i.e.,
Cytogenetic mechanisms in the progression from low-grade to high-grade GIST
Most GISTs have 1 or more chromosomal deletions, and the cytogenetic profile in GISTs is quite different from that in histologic mimics such as leiomyoma and leiomyosarcoma (Table 1).Tumor Type Characteristic Cytogenetic Events Molecular Events Gastrointestinal stromal tumor Monosomies 14 and 22 Deletion of 1p KIT mutation Desmoid Deletion of 5q APC mutation Trisomies 8 and 20 Endometrial stromal
Summary
This review has outlined the considerable recent progress in our understanding of biological and genetic mechanisms in GISTs. Our intention has been to emphasize aspects of GIST “basic science” that are germane to the intriguing clinicopathologic features of GISTs. Our focus has been primarily on science and biological mechanisms rather than on clinical correlates. The relevance and application of these scientific advances, in the pathology and clinical fields, is discussed in several companion
Acknowledgements
The authors thank Nora Joseph and Dr. Anette Duensing, who provided figures for this review.
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Address correspondence and reprint requests to Jonathan A. Fletcher, MD, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.