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 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.

Automated summary

Loss of function of succinate dehydrogenase complex is a characteristic of 20-40% of KIT/PDGFRA-negative GIST. Half of SDH-deficient GIST patients lack SDHx mutations and are caused by hypermethylation of SDHC promoter. The remaining 50% have mutations in SDH subunits, with SDHA mutations being the most common.