title: Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center Philadelphia, PA, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Belinsky
authors.forename: Lori
authors.initials: L
authors.lastname: Rink
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
keywords: gastrointestinal stromal tumor; insulin-like growth factor receptor; review; succinate dehydrogenase; wild type