Skip to main content

Advertisement

SpringerLink
Log in

Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel–Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T>A, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C>T, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2α prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS-HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2α signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vortmeyer AO, Gnarra JR, Emmert-Buck MR, Katz D, Linehan WM, Oldfield EH, Zhuang Z (1997) von Hippel–Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel–Lindau disease. Hum Pathol 28:540–543

    Article  PubMed  CAS  Google Scholar 

  2. Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH (2004) Developmental effects of von Hippel–Lindau gene deficiency. Ann Neurol 55:721–728. doi:10.1002/ana.20090

    Article  PubMed  CAS  Google Scholar 

  3. Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G, Oldfield EH, Zhuang Z (2003) Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel–Lindau disease. Cancer Res 63:7051–7055

    PubMed  CAS  Google Scholar 

  4. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH (2010) Genetic analysis of von Hippel–Lindau disease. Hum Mutat 31:521–537. doi:10.1002/humu.21219

    PubMed  Google Scholar 

  5. Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T, Yao M (1994) Somatic mutations of the von Hippel–Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54:4845–4847

    PubMed  CAS  Google Scholar 

  6. Muscarella LA, la Torre A, Faienza A, Catapano D, Bisceglia M, D’Angelo V, Parrella P, Coco M, Fini G, Tancredi A, Zelante L, Fazio VM, D’Agruma L (2014) Molecular dissection of the VHL gene in solitary capillary hemangioblastoma of the central nervous system. J Neuropathol Exp Neurol 73:50–58. doi:10.1097/NEN.0000000000000024

    Article  PubMed  CAS  Google Scholar 

  7. Tse JY, Wong JH, Lo KW, Poon WS, Huang DP, Ng HK (1997) Molecular genetic analysis of the von Hippel–Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomas. Am J Clin Pathol 107:459–466

    PubMed  CAS  Google Scholar 

  8. Lee JY, Dong SM, Park WS, Yoo NJ, Kim CS, Jang JJ, Chi JG, Zbar B, Lubensky IA, Linehan WM, Vortmeyer AO, Zhuang Z (1998) Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 58:504–508

    PubMed  CAS  Google Scholar 

  9. Prowse AH, Webster AR, Richards FM, Richard S, Olschwang S, Resche F, Affara NA, Maher ER (1997) Somatic inactivation of the VHL gene in Von Hippel–Lindau disease tumors. Am J Hum Genet 60:765–771

    PubMed  CAS  PubMed Central  Google Scholar 

  10. Shankar GM, Taylor-Weiner A, Lelic N, Jones RT, Kim JC, Francis JM, Abedalthagafi M, Borges LF, Coumans JV, Curry WT, Nahed BV, Shin JH, Paek SH, Park SH, Stewart C, Lawrence MS, Cibulskis K, Thorner AR, Van Hummelen P, Stemmer-Rachamimov AO, Batchelor TT, Carter SL, Hoang MP, Santagata S, Louis DN, Barker FG, Meyerson M, Getz G, Brastianos PK, Cahill DP (2014) Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun 2:167. doi:10.1186/s40478-014-0167-x

    Article  PubMed  Google Scholar 

  11. Oberstrass J, Reifenberger G, Reifenberger J, Wechsler W, Collins VP (1996) Mutation of the Von Hippel–Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. J Pathol 179:151–156

    Article  PubMed  CAS  Google Scholar 

  12. Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G (1998) Germline mutation profile of the VHL gene in von Hippel–Lindau disease and in sporadic hemangioblastoma. Hum Mutat 12:424–430. doi:10.1002/(SICI)1098-1004(1998)12:6<424:AID-HUMU9>3.0.CO;2-H

    Article  PubMed  CAS  Google Scholar 

  13. Glasker S, Bender BU, Apel TW, van Velthoven V, Mulligan LM, Zentner J, Neumann HP (2001) Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. J Neurol Neurosurg Psychiatry 70:644–648

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Sprenger SH, Gijtenbeek JM, Wesseling P, Sciot R, van Calenbergh F, Lammens M, Jeuken JW (2001) Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization. J Neurooncol 52:241–247

    Article  PubMed  CAS  Google Scholar 

  15. Lemeta S, Pylkkanen L, Sainio M, Niemela M, Saarikoski S, Husgafvel-Pursiainen K, Bohling T (2004) Loss of heterozygosity at 6q is frequent and concurrent with 3p loss in sporadic and familial capillary hemangioblastomas. J Neuropathol Exp Neurol 63:1072–1079

    Article  PubMed  CAS  Google Scholar 

  16. Proescholdt MA, Mayer C, Kubitza M, Schubert T, Liao SY, Stanbridge EJ, Ivanov S, Oldfield EH, Brawanski A, Merrill MJ (2005) Expression of hypoxia-inducible carbonic anhydrases in brain tumors. Neuro-oncology 7:465–475. doi:10.1215/S1152851705000025

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Flamme I, Krieg M, Plate KH (1998) Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am J Pathol 153:25–29

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  PubMed  CAS  Google Scholar 

  19. Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS (2008) A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Eng J Med 358:162–168. doi:10.1056/NEJMoa073123

    Article  CAS  Google Scholar 

  20. Taieb D, Yang C, Delenne B, Zhuang Z, Barlier A, Sebag F, Pacak K (2013) First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab 98:E908–E913. doi:10.1210/jc.2013-1217

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z (2013) Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood 121:2563–2566. doi:10.1182/blood-2012-10-460972

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K (2012) Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 367:922–930. doi:10.1056/NEJMoa1205119

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Pacak K, Chew EY, Pappo AS, Yang C, Lorenzo FR, Wilson MW, Aronow MB, Young JA, Popovic V, Zhuang Z (2014) Ocular manifestations of hypoxia-inducible factor-2α paraganglioma-somatostatinoma-polycythemia syndrome. Ophthalmology. doi:10.1016/j.ophtha.2014.06.019

    PubMed  PubMed Central  Google Scholar 

  24. Pacak K, Jochmanova I, Prodanov T, Yang C, Merino MJ, Fojo T, Prchal JT, Tischler AS, Lechan RM, Zhuang Z (2013) New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 31:1690–1698. doi:10.1200/JCO.2012.47.1912

    Article  PubMed  PubMed Central  Google Scholar 

  25. Welander J, Andreasson A, Brauckhoff M, Backdahl M, Larsson C, Gimm O, Soderkvist P (2014) Frequent EPAS1/HIF2alpha exons 9 and 12 mutations in non-familial pheochromocytoma. Endocr Relat Cancer 21:495–504. doi:10.1530/ERC-13-0384

    Article  PubMed  CAS  Google Scholar 

  26. Comino-Mendez I, de Cubas AA, Bernal C, Alvarez-Escola C, Sanchez-Malo C, Ramirez-Tortosa CL, Pedrinaci S, Rapizzi E, Ercolino T, Bernini G, Bacca A, Leton R, Pita G, Alonso MR, Leandro-Garcia LJ, Gomez-Grana A, Inglada-Perez L, Mancikova V, Rodriguez-Antona C, Mannelli M, Robledo M, Cascon A (2013) Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Hum Mol Genet 22:2169–2176. doi:10.1093/hmg/ddt069

    Article  PubMed  CAS  Google Scholar 

  27. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr (2002) Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein. Cancer Cell 1:237–246

    Article  PubMed  CAS  Google Scholar 

  28. Lorenzo FR, Yang C, Ng Tang Fui M, Vankayalapati H, Zhuang Z, Huynh T, Grossmann M, Pacak K, Prchal JT (2013) A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med 91:507–512. doi:10.1007/s00109-012-0967-z

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser RR (2013) Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell Rep 3:52–59. doi:10.1016/j.celrep.2012.12.007

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Toledo RA, Qin Y, Srikantan S, Morales NP, Li Q, Deng Y, Kim SW, Pereira MA, Toledo SP, Su X, Aguiar RC, Dahia PL (2013) In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer 20:349–359. doi:10.1530/ERC-13-0101

    Article  PubMed  CAS  Google Scholar 

  31. Yan Q, Bartz S, Mao M, Li L, Kaelin WG Jr (2007) The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo. Mol Cell Biol 27:2092–2102. doi:10.1128/MCB.01514-06

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Jochmanova I, Yang C, Zhuang Z, Pacak K (2013) Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. J Natl Cancer Inst 105:1270–1283. doi:10.1093/jnci/djt201

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724. doi:10.1038/nature07943

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004. doi:10.1200/JCO.2004.05.061

    Article  PubMed  CAS  Google Scholar 

  35. Shively SB, Falke EA, Li J, Tran MG, Thompson ER, Maxwell PH, Roessler E, Oldfield EH, Lonser RR, Vortmeyer AO (2011) Developmentally arrested structures preceding cerebellar tumors in von Hippel–Lindau disease. Mod Pathol 24:1023–1030. doi:10.1038/modpathol.2011.61

    Article  PubMed  PubMed Central  Google Scholar 

  36. Rankin EB, Rha J, Unger TL, Wu CH, Shutt HP, Johnson RS, Simon MC, Keith B, Haase VH (2008) Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27:5354–5358. doi:10.1038/onc.2008.160

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22. doi:10.1038/nrc3183

    CAS  Google Scholar 

Download references

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, La Timone University Hospital & CERIMED & Inserm UMR1068 Marseille Cancerology Research Center, Institut Paoli-Calmettes, Aix-Marseille University, 264 RUE Saint-Pierre, 13385, Marseille, France

    David Taïeb

  2. Laboratory of Molecular Biology, Conception Hospital & CNRS, CRN2M UMR 7286, Aix-Marseille University, Marseille, France

    Anne Barlier & Morgane Pertuit

  3. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA

    Chunzhang Yang & Zhengping Zhuang

  4. Department of Neuropathology, La Timone University Hospital, Aix-Marseille University, Marseille, France

    Aurélie Tchoghandjian & Dominique Figarella-Branger

  5. Department of Endocrinology, La Timone University Hospital, Aix-Marseille University, Marseille, France

    Claire Rochette

  6. Department of Genetics, La Timone University Hospital, Aix-Marseille University, Marseille, France

    Hélène Zattara-Canoni

  7. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA

    Karel Pacak

  8. Department of Neurosurgery, La Timone University Hospital, Aix-Marseille University, Marseille, France

    Philippe Metellus

Authors
  1. David Taïeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne Barlier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunzhang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morgane Pertuit
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aurélie Tchoghandjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claire Rochette
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hélène Zattara-Canoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dominique Figarella-Branger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhengping Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karel Pacak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Philippe Metellus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Taïeb.

Ethics declarations

Conflict of interest

The authors have nothing to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taïeb, D., Barlier, A., Yang, C. et al. Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas. J Neurooncol 126, 473–481 (2016). https://doi.org/10.1007/s11060-015-1983-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-015-1983-y

Keywords

Search

Navigation