Vol 72, No 5 (2022)
Review paper
Published online: 2022-10-19

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SDH-deficient gastrointestinal stromal tumours

Piotr Rutkowski1, Katarzyna Seliga2, Maria Dębiec-Rychter3
Nowotwory. Journal of Oncology 2022;72(5):326-333.


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.

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