Frontiers in Oncology (May 2013)

Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors

  • Martin G. Belinsky,
  • Lori eRink,
  • Margaret evon Mehren

DOI
https://doi.org/10.3389/fonc.2013.00117
Journal volume & issue
Vol. 3

Abstract

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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 (IGF1R), 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 towards understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.

Keywords