Defects in succinate dehydrogenase in gastrointestinal stromal tumors lackingKITandPDGFRAmutations

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 inKITorPDGFRA(WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested forSDHgermline mutations. WT GISTs lacking demonstrableSDHgenetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined inKITmutant and neurofibromatosis-1–associated GIST, and complex II activity was also measured inSDH-deficient paraganglioma andKITmutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations inSDHBorSDHC. WT GISTs lacking somatic mutations or deletions inSDHsubunits had either complete loss of or substantial reduction in SDHB protein expression, whereas mostKITmutant 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-inactivatingSDHmutations. Testing for germline mutations inSDHis recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.