SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update

Genes · 4 authors, 3 centres

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TL;DR

This narrative review synthesizes published data on germline SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs). The central finding is that germline SDHA mutations are highly prevalent among SDHA-deficient GIST patients, supporting the importance of genetic counselling for carriers and their relatives.

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This narrative review summarizes literature on SDHA germline mutations in SDH-deficient GISTs, a subset comprising 20–40% of KIT/PDGFRA-negative GISTs. Approximately half of SDH-deficient GISTs are driven by SDHC promoter hypermethylation, while the remaining half harbor mutations in SDH subunits, with SDHA mutations being most common at approximately 30%. SDHA-mutant patients typically carry two mutational events at the SDHA locus. Implications center on the need for genetic counselling for SDHA-variant carriers and their relatives.

STUDY TYPE

narrative_review

SPECIALTY

oncology

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AI pipeline

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100% · A

ORIGINAL PAPER

PMC10048394

SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update

Genes

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ABSTRACT

Loss of function of the succinate dehydrogenase complex characterizes 20–40% of all KIT/PDGFRA -negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB , SDHC , and SDHD mutations in GIST occur in only 20–30% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA -mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA -mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA -variant carriers and relatives.

CITATION EXPORT

Angela Schipani, Margherita Nannini, Annalisa Astolfi et al.. SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update. Genes. (2023). https://doi.org/10.3390/genes14030646

AUTHORS

4 · 3 CENTRES

Angela Schipani, Margherita Nannini, Annalisa Astolfi, Maria A. Pantaleo

1Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
2Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CS Utrecht, The Netherlands
3Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy

EDITOR / REVIEWER

Andrzej Pławski, Szymon Hryhorowicz, Marta Kaczmarek-Rys, Tadeusz Dębníak