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, Suzanne George, Michael LaQuaglia, Alberto Pappo, Jonathan Trent, Margaret Von Mehren, Maureen O'Sullivan, Ronald R. De Krijger & 6 others Winand N M Dinjens, George D. Demetri, Cristina R. Antonescu, Jonathan A. Fletcher, Lee Helman, Constantine A. Stratakisc

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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.

Original languageEnglish
Pages (from-to)314-318
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number1
DOIs
StatePublished - Jan 4 2011
Externally publishedYes

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Gastrointestinal Stromal Tumors
Succinate Dehydrogenase
Mutation
Germ-Line Mutation
Paraganglioma
Electron Transport Complex II
Cell Respiration
Neurofibromatosis 1
Sequence Deletion
Carcinogenesis
Western Blotting
Immunohistochemistry

Keywords

  • Genetic predisposition
  • Pediatric
  • Sarcoma

ASJC Scopus subject areas

  • General

Cite this

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. / Janeway, Katherine A.; Kim, Su Young; Lodish, Maya; Nosé, Vânia; Rustin, Pierre; Gaal, José; Dahia, Patricia L M; Liegl, Bernadette; Ball, Evan R.; Raygada, Margarita; Lai, Angela H.; Kelly, Lorna; Hornick, Jason L.; George, Suzanne; LaQuaglia, Michael; Pappo, Alberto; Trent, Jonathan; Von Mehren, Margaret; O'Sullivan, Maureen; De Krijger, Ronald R.; Dinjens, Winand N M; Demetri, George D.; Antonescu, Cristina R.; Fletcher, Jonathan A.; Helman, Lee; Stratakisc, Constantine A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 1, 04.01.2011, p. 314-318.

Research output: Contribution to journalArticle

Janeway, KA, Kim, SY, Lodish, M, Nosé, V, Rustin, P, Gaal, J, Dahia, PLM, Liegl, B, Ball, ER, Raygada, M, Lai, AH, Kelly, L, Hornick, JL, George, S, LaQuaglia, M, Pappo, A, Trent, J, Von Mehren, M, O'Sullivan, M, De Krijger, RR, Dinjens, WNM, Demetri, GD, Antonescu, CR, Fletcher, JA, Helman, L & Stratakisc, CA 2011, 'Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 1, pp. 314-318. https://doi.org/10.1073/pnas.1009199108
Janeway, Katherine A. ; Kim, Su Young ; Lodish, Maya ; Nosé, Vânia ; Rustin, Pierre ; Gaal, José ; Dahia, Patricia L M ; Liegl, Bernadette ; Ball, Evan R. ; Raygada, Margarita ; Lai, Angela H. ; Kelly, Lorna ; Hornick, Jason L. ; George, Suzanne ; LaQuaglia, Michael ; Pappo, Alberto ; Trent, Jonathan ; Von Mehren, Margaret ; O'Sullivan, Maureen ; De Krijger, Ronald R. ; Dinjens, Winand N M ; Demetri, George D. ; Antonescu, Cristina R. ; Fletcher, Jonathan A. ; Helman, Lee ; Stratakisc, Constantine A. / Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 1. pp. 314-318.
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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.

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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.

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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.

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