SDH-deficient gastrointestinal stromal tumours

Abstract

Gastrointestinal stromal tumours (GIST) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GIST are induced by activating, mutually exclusive mutations of two genes -KIT and PDGFRA (platelet-derived growth factor receptor-alpha). However, approximately 10-15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumours are often called "wild type" (WT) GISTs. The SDH-deficient GISTs form a distinctive subset of tumours accounting for 20-40% of KIT/PDGFRA WT GIST, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4 to 7.7%. These tumours usually occur in the stomach (most commonly in the antrum) and have a spectrum of behaviour from indolent to progressive. In most cases the molecular mechanism behind the SDH-deficient GISTs is connected to germline mutations. SDHA germline mutations occur in approximately 30% of the SDH-deficient GIST, those in SDHB, SDHC, and SDHD appear in 20-30% of patients. The SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumour response to imatinib. Taking into account the biological features of SDH-deficient GIST, new therapies of potential interest comprise PI3K/AKT/mTOR inhibitors, heat-shock protein inhibitors, HIF1-α targeting agents, epigenetic modifiers and demethylating agents. However, further research is necessary in these fields.

Systemic mastocytosis, in the context of a deleterious germline SDHC variant, treated with ripretinib

“…Mutations in the genes encoding subunits of succinate dehydrogenase have been identified in patients with KIT -wild-type GIST and are thought to promote pathogenesis via a different mechanism by increasing the level of hypoxia-inducible factor-1 alpha and leading to the upregulation of its downstream molecules, such as insulin-like growth factor 1 and vascular endothelial growth factor receptor. 4 The role of germline SDHC mutations in SM is unknown and warrants further investigation.…”