Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase

Abstract

The discovery of activating mutations in the tyrosine kinase receptor genes KIT and PDGFRA has led to the development of effective targeted therapies for gastrointestinal stromal tumours (GISTs). Specific genotypes, in part, predict the response to treatment with tyrosine kinase inhibitors. However, ~10% of GISTs lack such mutations (often referred to as 'wild-type' GISTs). Recent insights into the biology of 'wild-type' GISTs have resulted in clinically significant subclassification of this heterogeneous group of tumours, a large subset of which are now known to represent succinate dehydrogenase-deficient GISTs. Recognition of this distinctive class of tumours has critical implications for prognosis, therapy, clinical follow-up, and genetic counselling. Other uncommon genetic groups include neurofibromatosis type I-associated and BRAF-mutant GISTs. This review provides an update on the diagnosis and pathogenesis of these less common classes of GISTs, summarizes the clinical and pathological features associated with particular genotypes, and discusses mechanisms of resistance to targeted therapies.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…41 Most SDH-deficient GISTs encompass tumors arising in Carney-Stratakis syndrome and the Carney triad, in pediatric GISTs, and in a subset of apparently sporadic KIT/PDGFRA WT GISTs. 41,42 These GISTs are characterized by unique clinicopathological features and biological properties: (i) female preponderance; (ii) gastric location (predilection for the distal stomach/antrum); (iii) common multifocality; (iv) a multinodular/plexiform growth pattern; (v) epithelioid cytomorphology, either pure or combined with a spindle-cell component; (vi) SDHA and/or SDHB immunonegativity; (vii) KIT (and DOG1) immunopositivity despite the lack of KIT/PDGFRA mutations; (viii) metastatic potential (often to lymph nodes); (ix) a relatively indolent clinical course, even in the presence of metastatic disease; and (x) insensitivity to imatinib. 41,42 With regard to RCCs and PAs, the number of reported mutations is too low (30 and 10, respectively) to draw reliable conclusions about any potential genotype-phenotype correlations, although it must be noted that 83% of the mutations identified in RCCs occurred in SDHB (Figure 1a).…”

Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells

“…As its activity in islets is~85% lower than that in liver or exocrine pancreatic tissue [2], it may represent one of the rate limiting steps of insulin secretion. Mutations of SDH have been linked to severe diseases, such as neuronal and neuroendocrine tumours [4][5][6]. For Huntington's disease (HD), defects in complex II, III and IV of the respiratory chain have been shown in post-mortem studies [7].…”

The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival

“…Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract, representing 10-20 cases per million in the world [1][2][3]. GISTs present driver oncogenic mutations of receptor tyrosine kinases KIT and PDGFRA and, less frequently, of the BRAF signal transduction molecule [4][5][6].…”