LAUSR

Simple Summary Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors classified primarily as soft tissue sarcomas and characteristically arise from the intestinal pacemaker cells of Cajal responsible for the gastrointestinal tract motility. They comprise a heterogenous group of tumors due to a variety of molecular alterations, mostly KIT (60–70%) or PDGFRA (10–15%) mutations, but also more rare alterations, including inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also gene fusions. Here, we review the most recent data on the molecular profile of GISTs and highlight systemic therapeutic implications according to distinct GIST molecular subtypes. Abstract Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60–70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10–15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.