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

Loss of function of the succinate dehydrogenase complex characterizes 20-40% of all -negative GIST. Approximately half of SDH-deficient GIST patients lack mutations and are caused by a hypermethylation of the promoter, which causes the repression of 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 mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. , , and mutations in GIST occur in only 20-30% of cases and most of these SDH mutations are germline. More recently, germline mutations in have also been described in several patients with loss of function of the SDH complex. -mutant patients usually carry two mutational events at the 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 -mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor somatic mutations, and offers a view towards understanding the importance of genetic counselling for -variant carriers and relatives.