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Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors

Martin G Belinsky1, Lori Rink, Margaret von Mehren

  • 1Department of Medical Oncology, Fox Chase Cancer Center Philadelphia, PA, USA.

Frontiers in Oncology
|June 5, 2013
PubMed

Insights

Gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations are often succinate dehydrogenase (SDH)-deficient. This review explores the molecular, pathological, and clinical links in these challenging wild-type GISTs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Most adult gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA mutations, responding to targeted therapies.
  • A subset of wild-type (WT) GISTs, prevalent in pediatric cases, lacks these mutations and shows poor response to kinase inhibitors.
  • WT GISTs exhibit distinct clinical, pathological, and molecular features, including insulin-like growth factor-1 receptor (IGF-1R) overexpression and succinate dehydrogenase (SDH) deficiency.

Purpose of the Study:

  • To review the molecular, pathological, and clinical connections in SDH-deficient GISTs.
  • To elucidate the underlying biology of WT GISTs.
  • To highlight therapeutic challenges associated with SDH-deficient GISTs.

Main Methods:

  • Literature review of studies on GIST molecular characteristics, pathology, and clinical features.
  • Analysis of transcriptional profiles and enzyme activity in GIST samples.
  • Examination of genetic alterations in SDH subunit genes.

Main Results:

  • SDH-deficient GISTs represent a distinct subclass of WT GISTs.
  • These tumors often result from bi-allelic inactivation of SDH subunit genes, particularly SDHA.
  • Overexpression of IGF-1R is a common molecular feature.

Conclusions:

  • SDH deficiency is a unifying characteristic of a subset of GISTs.
  • Understanding the biology of SDH-deficient GISTs is crucial for developing effective therapeutic strategies.
  • Targeting pathways beyond KIT/PDGFRA is necessary for treating these resistant GISTs.
Keywords:
gastrointestinal stromal tumorinsulin-like growth factor receptorreviewsuccinate dehydrogenasewild type

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