Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Abstract

Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.genetic predisposition | sarcoma | pediatric

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

“…[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.…”

“…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.…”

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.…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Since the initial discovery of SDHD mutations in 2000, mutations in SDHB and SDHC , and more recently, SDHA and SDHAF2 (encoding the protein responsible for FAD incorporation into SDH) have been identified with the same syndrome 47, 48, 49, 60. These mutations are found as heterozygous germline mutations, which means that loss of protein function and neoplastic transformation develops as a result of loss of heterozygosity, resulting in the complete loss of enzyme function by a second ‘hit.’61 Inactivating mutations of SDH subunits have since been reportedly associated with other tumor types including gastrointestinal stromal tumors,62 renal cell carcinoma,63, 64 and neuroblastoma 65, 66. Interestingly, mutations of SDHB predispose to a more malignant and aggressive form of paraganglioma than those of the other subunits, despite the apparent similarities in both functional and downstream phenotypic consequences of this mutation.…”