Familial Cancer

, Volume 13, Issue 3, pp 507–511 | Cite as

Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies

  • R. Renella
  • J. Carnevale
  • K. A. Schneider
  • J. L. Hornick
  • H. Q. Rana
  • K. A. Janeway
Short Communication


The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHx) lead to a number of inherited endocrine cancer predisposition syndromes, including familial paraganglioma/pheochromocytoma. Recent studies suggest a possible role for the SDH complex and other mitochondrial enzymes in the pathogenesis of hematological malignancy. Our aim was to search and identify pedigrees of patients affected by germline SHDx mutations treated at our institution for endocrine and other tumors, and seek to identify cases of hematological malignancy. We also analyzed cancer genome databases for reported cases of SDHx mutations outside of endocrine neoplasms. We report of two unrelated pedigrees carrying SDHx mutations with members affected by lymphomas. Sequencing data revealed one case of chronic lymphocytic leukemia with a SDHB mutation. This novel set of observations demonstrates the need for collaborative databases of patients with endocrine cancers with SDHx mutations, and the investigation of their role in hematological (lymphoid) malignancy.


Lymphoma Malignancy Cancer predisposition Succinate dehydrogenase 


Conflict of interest

The authors have no conflict of interest to disclose.


  1. 1.
    Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287(5454):848–851PubMedCrossRefGoogle Scholar
  2. 2.
    Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26(3):268–270. doi: 10.1038/81551 PubMedCrossRefGoogle Scholar
  3. 3.
    Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69(1):49–54. doi: 10.1086/321282 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI, Jahromi MS, Xekouki P, Szarek E, Walker RL, Lasota J, Raffeld M, Klotzle B, Wang Z, Jones L, Zhu Y, Wang Y, Waterfall JJ, O'Sullivan MJ, Bibikova M, Pacak K, Stratakis C, Janeway KA, Schiffman JD, Fan J-B, Helman L, Meltzer PS (2013) Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 3(6):648–657. doi: 10.1158/2159-8290.CD-13-0092
  5. 5.
    Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11(2):144–149. doi: 10.1038/ng1095-144 PubMedCrossRefGoogle Scholar
  6. 6.
    King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25(34):4675–4682. doi: 10.1038/sj.onc.1209594 PubMedCrossRefGoogle Scholar
  7. 7.
    Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER (2008) Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 100(17):1260–1262. doi: 10.1093/jnci/djn254 PubMedCrossRefGoogle Scholar
  8. 8.
    Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292(8):943–951. doi: 10.1001/jama.292.8.943 PubMedCrossRefGoogle Scholar
  9. 9.
    Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RJ (2011) Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol 35(10):1578–1585. doi: 10.1097/PAS.0b013e318227e7f4 PubMedCrossRefGoogle Scholar
  10. 10.
    Letouzé E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reyniès A, Gimenez-Roqueplo A-P, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23(6):739–752. doi: 10.1016/j.ccr.2013.04.018 PubMedCrossRefGoogle Scholar
  11. 11.
    Baysal BE (2007) A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia. PLoS ONE 2(5):e436. doi: 10.1371/journal.pone.0000436 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, Pediatric NIH, Wild-Type GC, O’Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 108(1):314–318. doi: 10.1073/pnas.1009199108 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 39(Database issue):D945–950. doi: 10.1093/nar/gkq929 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, Vartanov A, Fernandes SM, Saksena G, Cibulskis K, Tesar B, Gabriel S, Hacohen N, Meyerson M, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (2013) Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152(4):714–726. doi: 10.1016/j.cell.2013.01.019 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul J-L, Strompf L, Schlumberger M, Bertagna X, Plouin P-F, Jeunemaitre X, Gimenez-Roqueplo A-P (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23(34):8812–8818. doi: 10.1200/JCO.2005.03.1484 PubMedCrossRefGoogle Scholar
  16. 16.
    Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314PubMedCrossRefGoogle Scholar
  17. 17.
    Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL, Simon MC, Thompson CB (2007) The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 21(9):1037–1049. doi: 10.1101/gad.1529107 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7(1):77–85. doi: 10.1016/j.ccr.2004.11.022 PubMedCrossRefGoogle Scholar
  19. 19.
    Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38):23757–23763PubMedGoogle Scholar
  20. 20.
    Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11(5):407–420. doi: 10.1016/j.ccr.2007.04.001 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • R. Renella
    • 1
    • 5
    • 6
  • J. Carnevale
    • 1
  • K. A. Schneider
    • 2
  • J. L. Hornick
    • 3
    • 5
  • H. Q. Rana
    • 4
    • 5
  • K. A. Janeway
    • 1
    • 5
  1. 1.Department of Pediatric OncologyDana Farber Cancer InstituteBostonUSA
  2. 2.Pediatric Cancer Risk Program (PCRP)Dana-Farber Cancer InstituteBostonUSA
  3. 3.Department of PathologyBrigham and Women’s HospitalBostonUSA
  4. 4.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  5. 5.Harvard Medical SchoolBostonUSA
  6. 6.Department of Pediatric OncologyDana Farber Cancer InstituteBostonUSA

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