{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:46:06Z","timestamp":1792431966785,"version":"4.5.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,1,4]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>KIT<\/jats:italic>\n                    or\n                    <jats:italic>PDGFRA<\/jats:italic>\n                    (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for\n                    <jats:italic>SDH<\/jats:italic>\n                    germline mutations. WT GISTs lacking demonstrable\n                    <jats:italic>SDH<\/jats:italic>\n                    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\n                    <jats:italic>KIT<\/jats:italic>\n                    mutant and neurofibromatosis-1\u2013associated GIST, and complex II activity was also measured in\n                    <jats:italic>SDH<\/jats:italic>\n                    -deficient paraganglioma and\n                    <jats:italic>KIT<\/jats:italic>\n                    mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in\n                    <jats:italic>SDHB<\/jats:italic>\n                    or\n                    <jats:italic>SDHC<\/jats:italic>\n                    . WT GISTs lacking somatic mutations or deletions in\n                    <jats:italic>SDH<\/jats:italic>\n                    subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most\n                    <jats:italic>KIT<\/jats:italic>\n                    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\n                    <jats:italic>SDH<\/jats:italic>\n                    mutations. Testing for germline mutations in\n                    <jats:italic>SDH<\/jats:italic>\n                    is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1009199108","type":"journal-article","created":{"date-parts":[[2010,12,20]],"date-time":"2010-12-20T23:23:52Z","timestamp":1292887432000},"page":"314-318","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":562,"title":["Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking\n                    <i>KIT<\/i>\n                    and\n                    <i>PDGFRA<\/i>\n                    mutations"],"prefix":"10.1073","volume":"108","author":[{"given":"Katherine A.","family":"Janeway","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology-Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Lodish","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics, Program on Developmental Endocrinology Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e2nia","family":"Nos\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Rustin","sequence":"additional","affiliation":[{"name":"Inserm U676 and Universit\u00e9 Paris 7, Facult\u00e9 de M\u00e9decine Denis Diderot, IFR02 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Gaal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Josephine Nefkens Institute, Erasmus MC\u2014University Medical Center, 3000 CA, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia L. M.","family":"Dahia","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Liegl","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical University, 8036 Graz, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan R.","family":"Ball","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics, Program on Developmental Endocrinology Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Raygada","sequence":"additional","affiliation":[{"name":"Program on Developmental Endocrinology Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela H.","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology-Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna","family":"Kelly","sequence":"additional","affiliation":[{"name":"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L.","family":"Hornick","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"NIH Pediatric and Wild-Type GIST Clinic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland;"},{"name":"Histology Laboratory, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald R.","family":"de Krijger","sequence":"additional","affiliation":[{"name":"Department of Pathology, Josephine Nefkens Institute, Erasmus MC\u2014University Medical Center, 3000 CA, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winand N. M.","family":"Dinjens","sequence":"additional","affiliation":[{"name":"Department of Pathology, Josephine Nefkens Institute, Erasmus MC\u2014University Medical Center, 3000 CA, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George D.","family":"Demetri","sequence":"additional","affiliation":[{"name":"Ludwig Center, Dana-Farber\/Harvard Cancer Center, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina R.","family":"Antonescu","sequence":"additional","affiliation":[{"name":"Departments of sPathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Helman","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A.","family":"Stratakis","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics, Program on Developmental Endocrinology Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,12,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-006-9177-7"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5350.577"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079666"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-1938"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.05.140"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1984"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69446-4"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020461"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"5360","DOI":"10.1200\/JCO.2008.17.4284","article-title":"Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group","volume":"26","author":"Heinrich MC","year":"2008","unstructured":"MC Heinrich, et al., Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 26, 5360\u20135367 (2008).","journal-title":"J Clin Oncol"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21909"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.15.7461"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-2504"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.03.1484"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1737"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70164-0"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175689"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2245"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70007-3"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10235"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201904"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc071191"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-6-39"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-003-0938-0"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.10.e64"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.1144"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.07.011"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2315"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.16.2057"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2178"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181d6150d"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000172190.79552.8b"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq206"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70007-3"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2170"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e318186b158"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2382"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/81551"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1086\/324413"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-020525"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1353.014"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0010008"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207525"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2006.05.034"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1009199108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:50:41Z","timestamp":1649793041000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1009199108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,12,20]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,1,4]]}},"alternative-id":["10.1073\/pnas.1009199108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1009199108","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.8554956.9038054","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,12,20]]},"assertion":[{"value":"2010-12-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}