Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD

Abstract

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and plateletderived growth factor receptor-a (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

“…11,13 In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. 11,12,25,26 Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for o15% of cases. 12,14 However, mutational analysis of SDHA is seldom performed because of the complex structure of the gene with 15 exons and because of the presence of 3 pseudogenes that make sequencing the proper gene challenging.…”

“…[5][6][7] More recently, these tumors have been subcategorized into genetically defined subgroups, including tumors with activating mutations in BRAF, [8][9][10] loss-offunction mutations in NF1, or loss-of-function mutations in components of the inner mitochondrial membrane Krebs cycle enzyme complex succinate dehydrogenase (SDH). 11,12 This latter group of tumors has been designated 'SDH-deficient GIST'. 13,14 The observed distinctions in molecular genotype have important implications for the biological properties of the tumor, as well as sensitivity to targeted therapies.…”

“…13,15 The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. 16 Germline mutations in these genes have been identified in patients with paraganglioma, [17][18][19][20][21][22] renal cell carcinoma, 23,24 and GIST, 11,12 as well as syndromes of multiple tumor types. 11,13 In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA.…”

“…16 Germline mutations in these genes have been identified in patients with paraganglioma, [17][18][19][20][21][22] renal cell carcinoma, 23,24 and GIST, 11,12 as well as syndromes of multiple tumor types. 11,13 In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. 11,12,25,26 Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for o15% of cases.…”

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…Mutations in all four SDH genes have been demonstrated in gastric 'wild-type' GISTs. [13][14][15][16][17] Recent studies have identified SDHA as the most commonly mutated subunit, with SDHA mutations found in approximately 30% of SDHdeficient GISTs. [18][19][20][21] However, around 40% of SDH-deficient GISTs lack demonstrable mutations in an SDH subunit gene.…”