Abstract
Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called quadruple wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in quadruple WT, SDH-deficient, or KIT-mutant GISTs.
Highlights
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal (ICCs) or their precursors
The aim of this review is to report all current data about the FGFR pathway deregulation in GISTs, focusing on the current clinical implications and future perspectives
For example FGFR1 amplification is recurrently seen in less than 20% of squamous non-small-cell lung carcinoma (NSCLC) and breast cancer, while somatic activating mutations are more common in FGFR2 and FGFR3, with FGFR2 mutations involving 10–12% of endometrial carcinomas and approximately 4% of NSCLCs and gastric cancers, and FGFR3 being highly recurrent in urothelial carcinomas [24,46,47]
Summary
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. The fibroblast growth factor signaling pathway relies on a family of receptor tyrosine kinases (FGFR) and eighteen extracellular ligands (FGFs) and has been implicated in the oncogenic process of different tumor histotypes It regulates many physiological processes, in both the embryonic and adult stages of development, such as tissue differentiation and homeostasis, angiogenesis, and wound healing [24]. FGFs,fothr heignhaatifvfineitlyigraecnedptsoor fbiFnGdinFgr[e4c3e].ptors, belong to a family that includes 22 members identified by sequence homology, which were grouped into subfamilies based on function or phylogenetic relation Eighteen of these ligands encode molecules known to signal through FGF tyrosine kinase receptors. The extensive molecular characterization of quadruple WT GISTs in search of the causal oncogenic event was the driving force for the identification of activating alterations in FGF receptors, including point mutations and gene fusions, and of FGFR ligand overexpression (Table 1)
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