Gastrointestinal stromal tumours: origin and molecular oncology

Gastrointestinal stromal tumours (GISTs) are a family of tumours thought to arise from the interstitial cells of Cajal in the gastrointestinal tract. Recently, the putative stem and progenitor cells for GISTs have been identified.Most GISTs have oncogenic mutations in either KIT or platelet-derived growth factor receptor-α (PDGFRA), and targeting these mutant proteins with kinase inhibitors is effective in patients with advanced disease. There is substantial evidence that these mutations are pathogenetic for the initiation of GISTs.GISTs lacking KIT or PDGFRA mutations (known as wild-type GISTs) are a heterogeneous group, of which some have alterations in BRAF, RAS or in the genes of the succinate dehydrogenase complex.Classification of GISTs on the basis of molecular defects is relevant to the clinical management of patients. Notably, the response to kinase inhibitor therapy is influenced by the primary kinase genotype.Secondary mutations in KIT or PDGFRA eventually lead to drug resistance in most patients.A subpopulation of GIST cells with stem cell-like characteristics may be less sensitive to kinase inhibitors, providing the seed for drug resistance.