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.
