Succinate dehydrogenase-deficient gastrointestinal stromal tumors.
Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.
Ya-Mei Wang, Meng-Li Gu, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
Ya-Mei
YM
Wang
Ya-Mei Wang, Meng-Li Gu, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
Meng-Li
ML
Gu
Ya-Mei Wang, Meng-Li Gu, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
Feng
F
Ji
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D058990:Molecular Targeted Therapy; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D013385:Succinate Dehydrogenase; D017526:Receptor, IGF Type 1; D040262:Receptors, Vascular Endothelial Growth Factor
Gastrointestinal stromal tumors; Hypoxia-inducible factor 1α; Insulin-like growth factor 1 receptor; Succinate dehydrogenase; Vascular endothelial growth factor receptor