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Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations
Katherine A. Janeway, Su Young Kim, Maya Lodish, Vânia Nosé, Pierre Rustin, José Gaal, Patricia L. M. Dahia, Bernadette Liegl, Evan R. Ball, Margarita Raygada, Angela H. Lai, Lorna Kelly, Jason L. Hornick, NIH Pediatric, Wild-Type GIST Clinic, Maureen O'Sullivan, Ronald R. de Krijger, Winand N. M. Dinjens, George D. Demetri, Cristina R. Antonescu, Jonathan A. Fletcher, Lee Helman, Constantine A. Stratakis and Stuart H. Orkin
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 1 (January 4, 2011), pp. 314-318
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25770770
Page Count: 5
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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 immuno-histochemistry 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.
Proceedings of the National Academy of Sciences of the United States of America © 2011 National Academy of Sciences