TY - JOUR
T1 - Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations
AU - Janeway, Katherine A.
AU - Kim, Su Young
AU - Lodish, Maya
AU - Nosé, Vânia
AU - Rustin, Pierre
AU - Gaal, José
AU - Dahia, Patricia L.M.
AU - Liegl, Bernadette
AU - Ball, Evan R.
AU - Raygada, Margarita
AU - Lai, Angela H.
AU - Kelly, Lorna
AU - Hornick, Jason L.
AU - George, Suzanne
AU - LaQuaglia, Michael
AU - Pappo, Alberto
AU - Trent, Jonathan
AU - Von Mehren, Margaret
AU - O'Sullivan, Maureen
AU - De Krijger, Ronald R.
AU - Dinjens, Winand N.M.
AU - Demetri, George D.
AU - Antonescu, Cristina R.
AU - Fletcher, Jonathan A.
AU - Helman, Lee
AU - Stratakisc, Constantine A.
PY - 2011/12/4
Y1 - 2011/12/4
N2 - 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.
AB - 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.
KW - Adolescent
KW - Blotting, Western
KW - Cell Respiration/genetics
KW - DNA Mutational Analysis
KW - Electron Transport Complex II/genetics
KW - Gastrointestinal Stromal Tumors/enzymology
KW - Genetic Predisposition to Disease/genetics
KW - Germ-Line Mutation/genetics
KW - Humans
KW - Immunohistochemistry
KW - Paraganglioma/enzymology
KW - Polymorphism, Single Nucleotide
KW - Protein Subunits/genetics
KW - Proto-Oncogene Proteins c-kit/genetics
KW - Receptor, Platelet-Derived Growth Factor alpha/genetics
KW - Succinate Dehydrogenase/genetics
KW - Syndrome
UR - http://www.scopus.com/inward/record.url?scp=78651082042&partnerID=8YFLogxK
U2 - 10.1073/pnas.1009199108
DO - 10.1073/pnas.1009199108
M3 - Article
C2 - 21173220
AN - SCOPUS:78651082042
SN - 0027-8424
VL - 108
SP - 314
EP - 318
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -