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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
DOI: 10.5603/NJO.2022.0052
·
Nowotwory. Journal of Oncology 2022;72(5):326-333.
Affiliations
  1. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  2. Molecular and Translational Oncology Department, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  3. Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium

open access

Vol 72, No 5 (2022)
Rare neoplasms in oncology
Published online: 2022-10-19

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.

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.

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Keywords

gastrointestinal stromal tumour; SDH-deficient GIST; Carney Triad; Carney-Stratakis syndrome; TKI; SDHA/SDHB/SDHC/SDHD mutations; targeted therapy; imatinib; regorafenib

About this article
Title

SDH-deficient gastrointestinal stromal tumours

Journal

Nowotwory. Journal of Oncology

Issue

Vol 72, No 5 (2022)

Article type

Review paper

Pages

326-333

Published online

2022-10-19

Page views

142

Article views/downloads

51

DOI

10.5603/NJO.2022.0052

Bibliographic record

Nowotwory. Journal of Oncology 2022;72(5):326-333.

Keywords

gastrointestinal stromal tumour
SDH-deficient GIST
Carney Triad
Carney-Stratakis syndrome
TKI
SDHA/SDHB/SDHC/SDHD mutations
targeted therapy
imatinib
regorafenib

Authors

Piotr Rutkowski
Katarzyna Seliga
Maria Dębiec-Rychter

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