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.

Fig. 1.

(A) Representative H&E stains (Left) and corresponding SDHB IHC (Right) in KIT mutant (Top), SDH mutant (Middle), and WT GIST (Bottom), highlighting strong SDHB immunoexpression in the KIT mutant GIST and absence of SDHB expression in the SDH mutant GIST and the WT GIST. (B) Summary of SDHB IHC scores in pediatric (n = 14) and adult (n = 12) WT GIST, KIT mutant GIST (n = 15), and NF-1–associated GIST (n = 5).

Fig. 2.

Western blot of SDHB expression in KIT mutant and WT GIST. Cases marked by an asterisk had an SDHB IHC score of 0.

Fig. 3.

Assessment of complex II activity in a paraganglioma arising in a patient with a germline SDH mutation, in two WT GISTs, and in a KIT mutant GIST. Cytochrome c oxidase (complex IV), quinol cytochrome c reductase (complex III), NADH quinone reducatse (complex I), and ATPase (complex V) activities were normal in these tumors.