Endocrine Pathology

, Volume 17, Issue 2, pp 97–106 | Cite as

Recent insights into the molecular pathogenesis of pheochromocytoma and paraganglioma

  • Eijiro Nakamura
  • William G. KaelinJr.


Pheochromocytomas and paragangliomas are rare tumors derived from chromaffin cells. These tumors can arise in the context of hereditary cancer syndromes such as von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis 1. Recent studies indicate that germ line mutations of genes encoding specific succinate dehydrogenase (SDH) subunits also predispose individuals to pheochromocytomas and paragangliomas. This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development.

Key Words

Pheochromocytoma paragangliomas VHL RET NF1 SDH 


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  1. 1.
    DeLellis RA, Lloyd RV, Heitz PU, Eng, C, Pathology and Genetics of Tumors of Endocrine Organs. Lyon, France: IARC Press, 2004.Google Scholar
  2. 2.
    Baysal BE. Hereditary paraganglioma targets diverse paraganglia. J Med Genet 39:617–622, 2002.PubMedCrossRefGoogle Scholar
  3. 3.
    Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS, Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315–329, 2001.PubMedGoogle Scholar
  4. 4.
    Stein PP, Black HR, A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Medicine (Baltimore) 70:46–66, 1991.Google Scholar
  5. 5.
    Manger WM, Jr. Pheochromocytoma: a clinical overview. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis, and management. 2nd ed., Vol. 2. New York: Raven Press, 1995, 2225–2244, 1995.Google Scholar
  6. 6.
    Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466, 2002.PubMedCrossRefGoogle Scholar
  7. 7.
    Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329:1531–1538, 1993.PubMedCrossRefGoogle Scholar
  8. 8.
    Walther MM, Reiter R, Keiser HR, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 162: 659–664, 1999.PubMedCrossRefGoogle Scholar
  9. 9.
    Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276:1575–1579, 1996.PubMedCrossRefGoogle Scholar
  10. 10.
    Eng C., Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335:943–951, 1996.PubMedCrossRefGoogle Scholar
  11. 11.
    Riccardi VM, Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617–1627, 1981.PubMedCrossRefGoogle Scholar
  12. 12.
    Eng C ME. Dominant genes and phakomatoses associated with multiple primary cancers. In: Neugut AI, Meadows AT, Robinson E, eds. Multiple primary cancers, Philadelphia, PA: Lippincott Williams & Wilkins, 1999.Google Scholar
  13. 13.
    Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851, 2000.PubMedCrossRefGoogle Scholar
  14. 14.
    Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54, 2001.PubMedCrossRefGoogle Scholar
  15. 15.
    Niemann S, Muller U, Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26:268–270, 2000.PubMedCrossRefGoogle Scholar
  16. 16.
    Maher ER, Eng C, The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet 11:2347–2354, 2002.PubMedCrossRefGoogle Scholar
  17. 17.
    Gottlieb E, Tomlinson IP, Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866, 2005.PubMedCrossRefGoogle Scholar
  18. 18.
    Brauch H, Hoeppner W, Jahnig H, et al. Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene. J Clin Endocrinol Metab 82:4101–4104, 1997.PubMedCrossRefGoogle Scholar
  19. 19.
    Bar M, Friedman E, Jakobovitz O, et al. Sporadic phaeochro mocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes. Clin Endocrinol (Oxf) 47:707–712, 1997.CrossRefGoogle Scholar
  20. 20.
    Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 63:5615–5621, 2003.PubMedGoogle Scholar
  21. 21.
    Dannenberg H, De Krijger RR, van der Harst E, et al. Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas. Int J Cancer105:190–195, 2003.PubMedCrossRefGoogle Scholar
  22. 22.
    Eng C, Crossey PA, Mulligan LM, et al. Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet 32:934–937, 1995.PubMedCrossRefGoogle Scholar
  23. 23.
    Bender BU, Gutsche M, Glasker S, et al. Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab 85:4568–4574, 2000.PubMedCrossRefGoogle Scholar
  24. 24.
    Hofstra RM, Stelwagen T, Stulp RP, et al. Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J Clin Endocrinol Metab 81:2881–2884, 1996.PubMedCrossRefGoogle Scholar
  25. 25.
    Cho NH, Lee HW, Lim SY, Kang S, Jung WY, Park CS, Genetic aberrance of sporadic MEN 2A component tumours: analysis of RET. Pathology 37:10–13, 2005.PubMedCrossRefGoogle Scholar
  26. 26.
    Astuti D, Douglas F, Lennard TW, et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet 357:1181–1182, 2001.PubMedCrossRefGoogle Scholar
  27. 27.
    Gimm O, Armanios M, Dziema H, Neumann HP, Eng C, Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res 60:6822–6825, 2000.PubMedGoogle Scholar
  28. 28.
    Beldjord C, Desclaux-Arramond F, Raffin-Sanson M, et al., The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. J Clin Endocrinol Metab 80:2063–2068, 1995.PubMedCrossRefGoogle Scholar
  29. 29.
    Aguiar RC, Cox G, Pomeroy SL, Dahia PL. Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J Clin Endocrinol Metab 86:2890–2894, 2001.PubMedCrossRefGoogle Scholar
  30. 30.
    Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf) 59:728–733, 2003.CrossRefGoogle Scholar
  31. 31.
    Kaelin WG, Jr, The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun 338:627–638, 2005.PubMedCrossRefGoogle Scholar
  32. 32.
    Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J, HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1 alpha in normoxia. EMBO J 22:4082–4090, 2003.PubMedCrossRefGoogle Scholar
  33. 33.
    Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85, 2005.PubMedCrossRefGoogle Scholar
  34. 34.
    Kaelin WG Jr, Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682, 2002.PubMedCrossRefGoogle Scholar
  35. 35.
    Maher ER, Kaelin WG Jr, von Hippel-Lindau disease. Medicine (Baltimore) 76:381–391, 1997.CrossRefGoogle Scholar
  36. 36.
    Kim WY, Kaelin WG, Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004, 2004.PubMedCrossRefGoogle Scholar
  37. 37.
    Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG, Jr, Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237–246, 2002.PubMedCrossRefGoogle Scholar
  38. 38.
    Zimmer M, Doucette D, Siddiqui N, Iliopoulos O, Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL −/− tumors. Mol Cancer Res 2:89–95, 2004.PubMedGoogle Scholar
  39. 39.
    Kondo K, Kim WY, Lechpammer M, Kaelin WG, Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1:E83, 2003.PubMedCrossRefGoogle Scholar
  40. 40.
    Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD, The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1:247–255, 2002.PubMedCrossRefGoogle Scholar
  41. 41.
    Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WG Jr, von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10:1019–1027, 2001.PubMedCrossRefGoogle Scholar
  42. 42.
    Clifford SC, Cockman ME, Smallwood AC et al. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 10:1029–1038, 2001.PubMedCrossRefGoogle Scholar
  43. 43.
    Nakamura E, Abreu ELP, Awakura Y, et al. Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von hippel-lindau tumor suppressor protein. Am J Pathol 168:574–584, 2006.PubMedCrossRefGoogle Scholar
  44. 44.
    Lee S, Nakamura E, Yang H, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8:155–167, 2005.PubMedCrossRefGoogle Scholar
  45. 45.
    Pal S, Claffey KP, Dvorak HF, Mukhopadhyay D. The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J Biol Chem 272:27509–27512, 1997.PubMedCrossRefGoogle Scholar
  46. 46.
    Pal S, Claffey KP, Cohen HT, Mukhopadhyay D. Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C zeta. J Biol Chem 273:26277–26280, 1998.PubMedCrossRefGoogle Scholar
  47. 47.
    Okuda H, Hirai S, Takaki Y, et al. Direct interaction of the beta-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem Biophys Res Commun 263:491–497, 1999.PubMedCrossRefGoogle Scholar
  48. 48.
    Kieser A, Seitz T, Adler HS, et al. Protein kinase C-zeta reverts v-raf transformation of NIH-3T3 cells. Genes Dev 10:1455–1466, 1996.PubMedGoogle Scholar
  49. 49.
    Shaulian E, Karin M, AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–136, 2002.PubMedCrossRefGoogle Scholar
  50. 50.
    Eferl R, Wagner EF, AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868, 2003.PubMedCrossRefGoogle Scholar
  51. 51.
    Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R, Johnson EM, Jr, Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. J Cell Biol 127:1717–1727, 1994.PubMedCrossRefGoogle Scholar
  52. 52.
    Ham J, Babij C, Whitfield J, et al. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14:927–939, 1995.PubMedCrossRefGoogle Scholar
  53. 53.
    Schlingensiepen KH, Wollnik F, Kunst M, Schlingensiepen R, Herdegen T, Brysch W. The role of Jun transcription factor expression and phosphorylation in neuronal differentiation, neuronal cell death, and plastic adaptations in vivo. Cell Mol Neurobiol 14:487–505, 1994.PubMedCrossRefGoogle Scholar
  54. 54.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME, Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Sience 270:1326–1331, 1995.Google Scholar
  55. 55.
    Vogel KS, Brannan CI, Jenkins NA, Copeland NG, Parada LF, Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82:733–742, 1995.PubMedCrossRefGoogle Scholar
  56. 56.
    Tsui-Pierchala BA, Milbrandt J, Johnson EM, Jr. NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons. Neuron 33:261–273, 2002.PubMedCrossRefGoogle Scholar
  57. 57.
    Dechant G, Chat in the trophic web: NGF activates Ret by inter-RTK signaling. Neuron 33:156–158, 2002.PubMedCrossRefGoogle Scholar
  58. 58.
    Lipscomb EA, Sarmiere PD, Crowder RJ, Freeman RS. Expression of the SM-20 gene promotes death in nerve growth factor-dependent sympathetic neurons. J Neurochem 73:429–432, 1999.PubMedCrossRefGoogle Scholar
  59. 59.
    Lipscomb EA, Sarmiere PD, Freeman RS. SM-20 is a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons. J Biol Chem 276:5085–5092, 2001.PubMedCrossRefGoogle Scholar
  60. 60.
    Straub JA, Lipscomb EA, Yoshida ES, Freeman RS. Induction of SM-20 in PC12 cells leads to increased cytochrome c levels, accumulation of cytochrome c in the cytosol, and caspase-dependent cell death. J Neurochem 85:318–328, 2003.PubMedGoogle Scholar
  61. 61.
    del Peso L, Castellanos MC, Temes E, et al. The von Hippel Lindau/hypoxia-inducible factor (HIF) pathway regulates the transcription of the HIF-proline hydroxylase genes in response to low oxygen. J Biol Chem 278: 48690–48695, 2003.PubMedCrossRefGoogle Scholar
  62. 62.
    Aprelikova O, Chandramouli GV, Wood M, et al. Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. J Cell Biochem 92:491–501, 2004.PubMedCrossRefGoogle Scholar
  63. 63.
    Marxsen JH, Stengel P, Doege K, et al. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alphaprolyl-4-hydroxylases. Biochem J 381:761–767, 2004.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Eijiro Nakamura
    • 1
  • William G. KaelinJr.
    • 2
    • 3
  1. 1.Department of Urology, Graduate School of MedicineKyoto UniversityBoston
  2. 2.Dana-Farber Cancer InstituteHoward Hughes Medical InstituteBoston
  3. 3.Brigham and Women's HospitalHarvard Medical SchoolBoston

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