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.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the digestive tract, with an estimated annual incidence of 11–19.6 cases per million (Corless et al, 2011)
In 2008 we reported that insulin-like growth factor1 receptor (IGF1R) was over-expressed at the protein and RNA level in several adult wild type (WT) GIST samples, in comparison to mutant GISTs (Tarn et al, 2008)
While the progress made in the clinic with tyrosine kinase inhibitors (TKI) has been profound, patients whose GISTs are not well controlled have become the focus of ongoing investigations
Summary
Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the digestive tract, with an estimated annual incidence of 11–19.6 cases per million (Corless et al, 2011). CLINICAL FEATURES OF GISTs IN THE PEDIATRIC POPULATION Gastrointestinal stromal tumor in children typically presents in the second decade of life (median age of 13 years) with a strong predilection toward females, who represent ∼70–75% of sporadic pediatric cases (Benesch et al, 2009; Pappo and Janeway, 2009; Rink and Godwin, 2009) This gender bias seems to be developmentally related: in a series of 44 pediatric and young adults (5–21 years) with GIST originating in the stomach, essentially all patients under 16 years of age were girls (24/25, 96%), while the post-pubertal gender imbalance was less pronounced (11/19 females, 58%) (Miettinen et al, 2005a). Median age (years) Gender predilection Germline mutations Inheritance Anatomic distribution GIST histology
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