Gastrointestinal stromal tumors (GISTs) are clinically diagnosed by positive immunohistochemical staining of KIT, a type III receptor tyrosine kinase. Most GISTs contain gain-of-function, ie, oncogenic mutations in c-KIT or in platelet-derived growth factor receptor-alpha (PDGFR-alpha), which appears to be the major initiating event that drives the pathogenesis for GIST. Furthermore, mutations in either of these genes appear to be required for tumor growth and progression. This scenario can be thought of as "oncogenic addiction" and is one of the major reasons why some GISTs respond significantly to therapies that target these mutant receptors. In addition to mutations in c-KIT or PDGFR-alpha, genomic alterations contribute to disease progression. Moreover, GISTs that harbor different c-KIT or PDGFR-alpha mutations have different molecular signatures at the level of gene expression, which further contributes to the complexity of GIST biology and variable responses to treatment. This article will discuss the molecular basis of pathogenesis and genetic and genomic alterations that contribute to GIST tumorigenesis and disease progression as well as the heterogeneity of this disease.
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