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

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 depleti...

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Autores principales: Schipani, Angela, Nannini, Margherita, Astolfi, Annalisa, Pantaleo, Maria A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048394/
https://www.ncbi.nlm.nih.gov/pubmed/36980917
http://dx.doi.org/10.3390/genes14030646
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author Schipani, Angela
Nannini, Margherita
Astolfi, Annalisa
Pantaleo, Maria A.
author_facet Schipani, Angela
Nannini, Margherita
Astolfi, Annalisa
Pantaleo, Maria A.
author_sort Schipani, Angela
collection PubMed
description 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.
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spelling pubmed-100483942023-03-29 SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update Schipani, Angela Nannini, Margherita Astolfi, Annalisa Pantaleo, Maria A. Genes (Basel) Review 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. MDPI 2023-03-04 /pmc/articles/PMC10048394/ /pubmed/36980917 http://dx.doi.org/10.3390/genes14030646 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Schipani, Angela
Nannini, Margherita
Astolfi, Annalisa
Pantaleo, Maria A.
SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title_full SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title_fullStr SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title_full_unstemmed SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title_short SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
title_sort sdha germline mutations in sdh-deficient gists: a current update
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048394/
https://www.ncbi.nlm.nih.gov/pubmed/36980917
http://dx.doi.org/10.3390/genes14030646
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