Advertisement

Cell and Tissue Research

, Volume 372, Issue 2, pp 347–365 | Cite as

Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype

  • Stephanie M. J. Fliedner
  • Georg Brabant
  • Hendrik Lehnert
Review

Abstract

To date, germline or somatic genetic events can be detected for at least 60% of paragangliomas. Strong genotype–phenotype associations have been recognized and become increasingly refined. Characteristics closely linked with genotype include syndromic presentation, age of onset, risk of metastatic disease and predominant anatomic site. In contrast, profiles of catecholamine secretion appear to be largely determined by anatomic location or cell type of origin. This review summarizes current knowledge of genotype–phenotype correlations for paragangliomas in different locations and scrutinizes previous publications on the respective tissues of origin to find potential explanations for site-related differences. We hypothesize that differential sensitivities of distinct chromaffin cell populations to hypoxia are major determinants of these differences, with increased sensitivity to hypoxia likely exacerbating vulnerability to mutation-derived disruption of hypoxic signaling pathways. Potential involvement of endothelin-1, tumor necrosis factor type 1 receptor-associated protein and the hypoxia-inducible miR-210 in the development of abdomino-thoracic or head and neck paragangliomas are discussed. Recognition of factors that predispose to chromosomal losses, or amplify sub-threshold molecular alterations towards tumorigenic events in different (chromaffin) cell types, may facilitate the leap from developing targeted therapies towards establishment of tumor preventative measures.

Keywords

Paraganglioma Pheochromocytoma Chromaffin cell Differential tumor susceptibility Tumorigenic vulnerability 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Disclosure statement

The authors have nothing to disclose.

References

  1. 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 JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23:8812–8818PubMedCrossRefGoogle Scholar
  2. Amico JA, Clarke MR, Watson CG, Kim NB, Bononi PL, Crowley RS, Horwitz MJ (1993) Endothelin-1 gene expression in human pheochromocytoma. J Lab Clin Med 122:667–672PubMedGoogle Scholar
  3. Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E (2017) SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery 161:230–239PubMedCrossRefGoogle Scholar
  4. Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE (2003) Altitude is a phenotypic modifier in hereditary paraganglioma type 1: Evidence for an oxygen-sensing defect. Hum Genet 113:228–237PubMedCrossRefGoogle Scholar
  5. Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C (2011) Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: Primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96:717–725PubMedCrossRefGoogle Scholar
  6. Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, Ngeow J, Wellner U, Malinoc A, Taschin E, Barbon G, Lanza V, Soderkvist P, Stenman A, Larsson C, Svahn F, Chen JL, Marquard J, Fraenkel M, Walter MA, Peczkowska M, Prejbisz A, Jarzab B, Hasse-Lazar K, Petersenn S, Moeller LC, Meyer A, Reisch N, Trupka A, Brase C, Galiano M, Preuss SF, Kwok P, Lendvai N, Berisha G, Makay O, Boedeker CC, Weryha G, Racz K, Januszewicz A, Walz MK, Gimm O, Opocher G, Eng C, Neumann HP, European-American-Asian Pheochromocytoma-Paraganglioma Registry Study G (2017) Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention. JAMA Oncol 3:1204–1212 (in press)Google Scholar
  7. 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 287:848–851PubMedCrossRefGoogle Scholar
  8. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH 3rd, Myers EN, Ferrell RE, Rubinstein WS (2002) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39:178–183PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bishop T, Talbot NP, Turner PJ, Nicholls LG, Pascual A, Hodson EJ, Douglas G, Fielding JW, Smith TG, Demetriades M, Schofield CJ, Robbins PA, Pugh CW, Buckler KJ, Ratcliffe PJ (2013) Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol 591:3565–3577Google Scholar
  10. Bjorklund P, Pacak K, Crona J (2016) Precision medicine in pheochromocytoma and paraganglioma: Current and future concepts. J Intern Med 280:559–573PubMedCrossRefGoogle Scholar
  11. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K (2006) High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: Implications for genetic testing. J Clin Endocrinol Metab 91:4505–4509PubMedCrossRefGoogle Scholar
  12. Brown WJ, Barajas L, Waisman J, De Quattro V (1972) Ultrastructural and biochemical correlates of adrenal and extra-adrenal pheochromocytoma. Cancer 29:744–759PubMedCrossRefGoogle Scholar
  13. Buckler KJ, Turner PJ (2013) Oxygen sensitivity of mitochondrial function in rat arterial chemoreceptor cells. J Physiol 591:3549–3563PubMedPubMedCentralCrossRefGoogle Scholar
  14. Buffet A, Smati S, Mansuy L, Menara M, Lebras M, Heymann MF, Simian C, Favier J, Murat A, Cariou B, Gimenez-Roqueplo AP (2014) Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab 99:E369–E373PubMedCrossRefGoogle Scholar
  15. Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, de Quiros SB, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacche M, de Krijger RR, Ercolino T, Girerd X, Gomez-Garcia EB, Gomez-Grana A, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JW, Leton R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops CM, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M (2012) MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 18:2828–2837PubMedCrossRefGoogle Scholar
  16. Buttigieg J, Brown ST, Lowe M, Zhang M, Nurse CA (2008) Functional mitochondria are required for O2 but not CO2 sensing in immortalized adrenomedullary chromaffin cells. Am J Physiol Cell Physiol 294:C945–C956PubMedCrossRefGoogle Scholar
  17. Camenisch G, Stroka DM, Gassmann M, Wenger RH (2001) Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch 443:240–249PubMedCrossRefGoogle Scholar
  18. Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Curras-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Leton R, Gomez-Grana A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP (2014) Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23:2440–2446PubMedCrossRefGoogle Scholar
  19. Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E, Loriot C, Elarouci N, Morin A, Menara M, Lepoutre-Lussey C, Badoual C, Sibony M, Dousset B, Libe R, Zinzindohoue F, Plouin PF, Bertherat J, Amar L, de Reynies A, Favier J, Gimenez-Roqueplo AP (2015) Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun 6:6044PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chae YC, Angelin A, Lisanti S, Kossenkov AV, Speicher KD, Wang H, Powers JF, Tischler AS, Pacak K, Fliedner S, Michalek RD, Karoly ED, Wallace DC, Languino LR, Speicher DW, Altieri DC (2013) Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 4:2139PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chen J, He L, Dinger B, Stensaas L, Fidone S (2002) Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 282:L1314–L1323PubMedCrossRefGoogle Scholar
  22. Cleary S, Brouwers FM, Eisenhofer G, Pacak K, Christie DL, Lipski J, McNeil AR, Phillips JK (2005) Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma. Cell Tissue Res 322:443–453PubMedCrossRefGoogle Scholar
  23. 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 22:2169–2176PubMedCrossRefGoogle Scholar
  24. Cornog JL, Wilkinson JH, Arvan DA, Freed RM, Sellers AM, Barker C (1970) Extra-adrenal pheochromocytoma. Some electron microscopic and biochemical studies. Am J Med 48:654–660PubMedCrossRefGoogle Scholar
  25. Crona J, Backman S, Maharjan R, Mayrhofer M, Stalberg P, Isaksson A, Hellman P, Bjorklund P (2015) Spatiotemporal heterogeneity characterizes the genetic landscape of Pheochromocytoma and defines early events in tumorigenesis. Clin Cancer Res 21:4451–4460PubMedCrossRefGoogle Scholar
  26. Crona J, Delgado Verdugo A, Maharjan R, Stalberg P, Granberg D, Hellman P, Bjorklund P (2013) Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J Clin Endocrinol Metab 98:E1266–E1271PubMedCrossRefGoogle Scholar
  27. Curras-Freixes M, Inglada-Perez L, Mancikova V, Montero-Conde C, Leton R, Comino-Mendez I, Apellaniz-Ruiz M, Sanchez-Barroso L, Aguirre Sanchez-Covisa M, Alcazar V, Aller J, Alvarez-Escola C, Andia-Melero VM, Azriel-Mira S, Calatayud-Gutierrez M, Diaz JA, Diez-Hernandez A, Lamas-Oliveira C, Marazuela M, Matias-Guiu X, Meoro-Aviles A, Patino-Garcia A, Pedrinaci S, Riesco-Eizaguirre G, Sabado-Alvarez C, Saez-Villaverde R, Sainz de Los Terreros A, Sanz Guadarrama O, Sastre-Marcos J, Scola-Yurrita B, Segura-Huerta A, Serrano-Corredor Mde L, Villar-Vicente MR, Rodriguez-Antona C, Korpershoek E, Cascon A, Robledo M (2015) Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet 52:647–656PubMedCrossRefGoogle Scholar
  28. Dahia PL (2014) Pheochromocytoma and paraganglioma pathogenesis: Learning from genetic heterogeneity. Nat Rev Cancer 14:108–119PubMedCrossRefGoogle Scholar
  29. Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD (2005) A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1:72–80PubMedCrossRefGoogle Scholar
  30. Darr R, Nambuba J, Del Rivero J, Janssen I, Merino M, Todorovic M, Balint B, Jochmanova I, Prchal JT, Lechan RM, Tischler AS, Popovic V, Miljic D, Adams KT, Prall FR, Ling A, Golomb MR, Ferguson M, Nilubol N, Chen CC, Chew E, Taieb D, Stratakis CA, Fojo T, Yang C, Kebebew E, Zhuang Z, Pacak K (2016) Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome. Endocr Relat Cancer 23:899–908PubMedPubMedCentralCrossRefGoogle Scholar
  31. de Cubas AA, Leandro-Garcia LJ, Schiavi F, Mancikova V, Comino-Mendez I, Inglada-Perez L, Perez-Martinez M, Ibarz N, Ximenez-Embun P, Lopez-Jimenez E, Maliszewska A, Leton R, Gomez Grana A, Bernal C, Alvarez-Escola C, Rodriguez-Antona C, Opocher G, Munoz J, Megias D, Cascon A, Robledo M (2013) Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. Endocr Relat Cancer 20:477–493PubMedCrossRefGoogle Scholar
  32. Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, Prins FA, van Duinen SG, Taschner PE, van der Mey AG, Cornelisse CJ (2003) SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J Pathol 201:480–486PubMedCrossRefGoogle Scholar
  33. Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers FM, Lai EW, Adams KT, Pacak K (2005a) Biochemical and clinical manifestations of dopamine-producing paragangliomas: Utility of plasma methoxytyramine. J Clin Endocrinol Metab 90:2068–2075PubMedCrossRefGoogle Scholar
  34. Eisenhofer G, Huynh TT, Elkahloun A, Morris JC, Bratslavsky G, Linehan WM, Zhuang Z, Balgley BM, Lee CS, Mannelli M, Lenders JW, Bornstein SR, Pacak K (2008) Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma. Am J Physiol Endocrinol Metab 295:E1223–E1233PubMedPubMedCentralCrossRefGoogle Scholar
  35. Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG (2004) Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: Activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer 11:897–911PubMedCrossRefGoogle Scholar
  36. Eisenhofer G, Lenders JW, Goldstein DS, Mannelli M, Csako G, Walther MM, Brouwers FM, Pacak K (2005b) Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 51:735–744PubMedCrossRefGoogle Scholar
  37. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR (1999) Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 340:1872–1879PubMedCrossRefGoogle Scholar
  38. Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K, Timmers HJ, Pacak K (2012) Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 48:1739–1749PubMedCrossRefGoogle Scholar
  39. Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K (2011a) Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem 57:411–420PubMedPubMedCentralCrossRefGoogle Scholar
  40. Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK, Timmers HJ, Bornstein SR, Lenders JW (2011b) Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 18:97–111PubMedCrossRefGoogle Scholar
  41. Eisenhofer G, Timmers HJ, Lenders JW, Bornstein SR, Tiebel O, Mannelli M, King KS, Vocke CD, Linehan WM, Bratslavsky G, Pacak K (2011c) Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 96:375–384PubMedCrossRefGoogle Scholar
  42. Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K (2001) Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86:1999–2008PubMedCrossRefGoogle Scholar
  43. Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P, Giscos-Douriez I, De Reynies A, Bertherat J, Badoual C, Tissier F, Amar L, Libe R, Plouin PF, Jeunemaitre X, Rustin P, Gimenez-Roqueplo AP (2009) The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS ONE 4:e7094PubMedPubMedCentralCrossRefGoogle Scholar
  44. Favier J, Buffet A, Gimenez-Roqueplo AP (2012a) HIF2A mutations in paraganglioma with polycythemia. N Engl J Med 367:2161PubMedCrossRefGoogle Scholar
  45. Favier J, Igaz P, Burnichon N, Amar L, Libe R, Badoual C, Tissier F, Bertherat J, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP (2012b) Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma. Endocr Pathol 23:34–42PubMedCrossRefGoogle Scholar
  46. Favier J, Plouin PF, Corvol P, Gasc JM (2002) Angiogenesis and vascular architecture in pheochromocytomas: Distinctive traits in malignant tumors. Am J Pathol 161:1235–1246PubMedPubMedCentralCrossRefGoogle Scholar
  47. Fernandez-Aguera MC, Gao L, Gonzalez-Rodriguez P, Pintado CO, Arias-Mayenco I, Garcia-Flores P, Garcia-Perganeda A, Pascual A, Ortega-Saenz P, Lopez-Barneo J (2015) Oxygen sensing by arterial chemoreceptors depends on mitochondrial complex I signaling. Cell Metab 22:825–837PubMedCrossRefGoogle Scholar
  48. Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, Ling S, Jefferys SR, de Cubas AA, Wenz B, Korpershoek E, Amelio AL, Makowski L, Rathmell WK, Gimenez-Roqueplo AP, Giordano TJ, Asa SL, Tischler AS, Cancer Genome Atlas Research N, Pacak K, Nathanson KL, Wilkerson MD (2017) Comprehensive molecular characterization of Pheochromocytoma and Paraganglioma. Cancer Cell 31:181–193PubMedPubMedCentralCrossRefGoogle Scholar
  49. Fliedner SM, Breza J, Kvetnansky R, Powers JF, Tischler AS, Wesley R, Merino M, Lehnert H, Pacak K (2010) Tyrosine hydroxylase, chromogranin a, and steroidogenic acute regulator as markers for successful separation of human adrenal medulla. Cell Tissue Res 340:607–612PubMedPubMedCentralCrossRefGoogle Scholar
  50. Fliedner SM, Kaludercic N, Jiang XS, Hansikova H, Hajkova Z, Sladkova J, Limpuangthip A, Backlund PS, Wesley R, Martiniova L, Jochmanova I, Lendvai NK, Breza J, Yergey AL, Paolocci N, Tischler AS, Zeman J, Porter FD, Lehnert H, Pacak K (2012) Warburg effect’s manifestation in aggressive pheochromocytomas and paragangliomas: Insights from a mouse cell model applied to human tumor tissue. PLoS ONE 7:e40949PubMedPubMedCentralCrossRefGoogle Scholar
  51. Fliedner SM, Shankavaram U, Marzouca G, Elkahloun A, Jochmanova I, Daerr R, Linehan WM, Timmers H, Tischler AS, Papaspyrou K, Brieger J, de Krijger R, Breza J, Eisenhofer G, Zhuang Z, Lehnert H, Pacak K (2016) Hypoxia-inducible factor 2alpha mutation-related Paragangliomas classify as discrete Pseudohypoxic subcluster. Neoplasia 18:567–576PubMedPubMedCentralCrossRefGoogle Scholar
  52. Flynn A, Dwight T, Harris J, Benn D, Zhou L, Hogg A, Catchpoole D, James P, Duncan EL, Trainer A, Gill AJ, Clifton-Bligh R, Hicks RJ, Tothill RW (2016) Pheo-type: A diagnostic gene-expression assay for the classification of Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab 101:1034–1043PubMedCrossRefGoogle Scholar
  53. Gao J, Zhao L, Shahzad M, Zhang D, Liu G, Hou B, Li J (2013) Expression of endothelin-1 and its receptors in the lungs of broiler chickens exposed to high-altitude hypoxia. Avian Pathol 42:416–419PubMedCrossRefGoogle Scholar
  54. Gao L, Gonzalez-Rodriguez P, Ortega-Saenz P, Lopez-Barneo J (2017) Redox signaling in acute oxygen sensing. Redox Biol 12:908–915PubMedPubMedCentralCrossRefGoogle Scholar
  55. Ghayee HK, Havekes B, Corssmit EP, Eisenhofer G, Hammes SR, Ahmad Z, Tessnow A, Lazurova I, Adams KT, Fojo AT, Pacak K, Auchus RJ (2009) Mediastinal paragangliomas: Association with mutations in the succinate dehydrogenase genes and aggressive behavior. Endocr Relat Cancer 16:291–299PubMedCrossRefGoogle Scholar
  56. Gupta G, Pacak K, Committee AAS (2017) Precision medicine: An update on genotype/biochemical phenotype relationships in Pheochromocytoma/Paraganglioma patients. Endocr Pract 23:690–704PubMedCrossRefGoogle Scholar
  57. Gutmann DH, Cole JL, Stone WJ, Ponder BA, Collins FS (1994) Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. Genes Chromosomes Cancer 10:55–58PubMedCrossRefGoogle Scholar
  58. Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT (2008) Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 28:718–731PubMedCrossRefGoogle Scholar
  59. Hensen EF, Goeman JJ, Oosting J, Van der Mey AG, Hogendoorn PC, Cremers CW, Devilee P, Cornelisse CJ (2009) Similar gene expression profiles of sporadic, PGL2-, and SDHD-linked paragangliomas suggest a common pathway to tumorigenesis. BMC Med Genet 2:25Google Scholar
  60. Her YF, Nelson-Holte M, Maher LJ 3rd (2015) Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS ONE 10:e0127471PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hobert JA, Mester JL, Moline J, Eng C (2012) Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals. Genet Med 14:616–619PubMedPubMedCentralCrossRefGoogle Scholar
  62. Hoekstra AS, Hensen EF, Jordanova ES, Korpershoek E, van der Horst-Schrivers AN, Cornelisse C, Corssmit EP, Hes FJ, Jansen JC, Kunst HP, Timmers HJ, Bateman A, Eccles D, Bovee JV, Devilee P, Bayley JP (2017) Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL-related paragangliomas, but less significant in SDHB-related paragangliomas. Oncotarget 8:14525–14536PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hollinshead KE, Tennant DA (2016) Mitochondrial metabolic remodeling in response to genetic and environmental perturbations. Wiley Interdiscip Rev Syst Biol Med 8:272–285PubMedPubMedCentralCrossRefGoogle Scholar
  64. Hu J, Locasale JW, Bielas JH, O’Sullivan J, Sheahan K, Cantley LC, Vander Heiden MG, Vitkup D (2013) Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat Biotechnol 31:522–529PubMedPubMedCentralCrossRefGoogle Scholar
  65. Huang J, Lemire BD (2009) Mutations in the C. Elegans succinate dehydrogenase iron-sulfur subunit promote superoxide generation and premature aging. J Mol Biol 387:559–569PubMedCrossRefGoogle Scholar
  66. Ibanez M, Valderrama-Canales FJ, Maranillo E, Vazquez T, Pascual-Font A, McHanwell S, Sanudo J (2010) Human laryngeal ganglia contain both sympathetic and parasympathetic cell types. Clin Anat 23:673–682PubMedCrossRefGoogle Scholar
  67. Imperiale A, Moussallieh FM, Sebag F, Brunaud L, Barlier A, Elbayed K, Bachellier P, Goichot B, Pacak K, Namer IJ, Taieb D (2013) A new specific succinate-glutamate metabolomic hallmark in SDHx-related paragangliomas. PLoS ONE 8:e80539PubMedPubMedCentralCrossRefGoogle Scholar
  68. Khamaisi M, Toukan H, Axelrod JH, Rosenberger C, Skarzinski G, Shina A, Meidan R, Koesters R, Rosen S, Walkinshaw G, Mimura I, Nangaku M, Heyman SN (2015) Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor. Kidney Int 87:761–770PubMedCrossRefGoogle Scholar
  69. Kimura N, Sasano N, Miura Y, Kobayashi K (1984) Adrenal and extra-adrenal pheochromocytomas: An ultrastructural and formaldehyde-induced fluorescence study with catecholamine content. Tohoku J Exp Med 142:1–14PubMedCrossRefGoogle Scholar
  70. Korpershoek E, Stobbe CK, van Nederveen FH, de Krijger RR, Dinjens WN (2010) Intra-tumoral molecular heterogeneity in benign and malignant pheochromocytomas and extra-adrenal sympathetic paragangliomas. Endocr Relat Cancer 17:653–662PubMedCrossRefGoogle Scholar
  71. Kumar P, Prabhakar NR (2012) Peripheral chemoreceptors: Function and plasticity of the carotid body. Compr Physiol 2:141–219PubMedPubMedCentralGoogle Scholar
  72. Kummer W, Habeck JO (1992) Chemoreceptor A-fibres in the human carotid body contain tyrosine hydroxylase and neurofilament immunoreactivity. Neuroscience 47:713–725PubMedCrossRefGoogle Scholar
  73. Lendvai N, Pawlosky R, Bullova P, Eisenhofer G, Patocs A, Veech RL, Pacak K (2014) Succinate-to-fumarate ratio as a new metabolic marker to detect the presence of SDHB/D-related paraganglioma: Initial experimental and ex vivo findings. Endocrinology 155:27–32PubMedCrossRefGoogle Scholar
  74. Letizia C, De Toma G, Cerci S, Scuro L, De Ciocchis A, D’Ambrosio C, Massa R, Cavallaro A, Scavo D (1996) Plasma endothelin-1 levels in patients with aldosterone-producing adenoma and pheochromocytoma. Clin Exp Hypertens 18:921–931PubMedCrossRefGoogle Scholar
  75. Letouze 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 Reynies A, Gimenez-Roqueplo AP, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23:739–752PubMedCrossRefGoogle Scholar
  76. Lloyd RV, Sisson JC, Shapiro B, Verhofstad AA (1986) Immunohistochemical localization of epinephrine, norepinephrine, catecholamine-synthesizing enzymes, and chromogranin in neuroendocrine cells and tumors. Am J Pathol 125:45–54PubMedPubMedCentralGoogle Scholar
  77. Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, Munoz I, Schiavi F, Montero-Conde C, de Cubas AA, Ramires R, Landa I, Leskela S, Maliszewska A, Inglada-Perez L, de la Vega L, Rodriguez-Antona C, Leton R, Bernal C, de Campos JM, Diez-Tascon C, Fraga MF, Boullosa C, Pisano DG, Opocher G, Robledo M, Cascon A (2010) Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol 24:2382–2391PubMedPubMedCentralCrossRefGoogle Scholar
  78. Lussey-Lepoutre C, Buffet A, Gimenez-Roqueplo AP, Favier J (2017) Mitochondrial deficiencies in the predisposition to Paraganglioma. Metabolites 7:17Google Scholar
  79. Macias D, Fernandez-Aguera MC, Bonilla-Henao V, Lopez-Barneo J (2014) Deletion of the von Hippel-Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor-mediated adaptation to hypoxia. EMBO Mol Med 6:1577–1592PubMedPubMedCentralCrossRefGoogle Scholar
  80. Mannelli M, Castellano M, Schiavi F, Filetti S, Giacche M, Mori L, Pignataro V, Bernini G, Giache V, Bacca A, Biondi B, Corona G, Di Trapani G, Grossrubatscher E, Reimondo G, Arnaldi G, Giacchetti G, Veglio F, Loli P, Colao A, Ambrosio MR, Terzolo M, Letizia C, Ercolino T, Opocher G, Italian Pheochromocytoma/Paraganglioma Network (2009) Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 94:1541–1547PubMedCrossRefGoogle Scholar
  81. Martucci VL, Emaminia A, del Rivero J, Lechan RM, Magoon BT, Galia A, Fojo T, Leung S, Lorusso R, Jimenez C, Shulkin BL, Audibert JL, Adams KT, Rosing DR, Vaidya A, Dluhy RG, Horvath KA, Pacak K (2015) Succinate dehydrogenase gene mutations in cardiac paragangliomas. Am J Cardiol 115:1753–1759PubMedPubMedCentralCrossRefGoogle Scholar
  82. Martucci VL, Pacak K (2014) Pheochromocytoma and paraganglioma: Diagnosis, genetics, management, and treatment. Curr Probl Cancer 38:7–41PubMedPubMedCentralCrossRefGoogle Scholar
  83. McCormick RI, Blick C, Ragoussis J, Schoedel J, Mole DR, Young AC, Selby PJ, Banks RE, Harris AL (2013) miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br J Cancer 108:1133–1142PubMedPubMedCentralCrossRefGoogle Scholar
  84. Merlo A, Bernardo-Castineira C, Saenz-de-Santa-Maria I, Pitiot AS, Balbin M, Astudillo A, Valdes N, Scola B, Del Toro R, Mendez-Ferrer S, Piruat JI, Suarez C, Chiara MD (2017) Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate. Oncotarget 8:6700–6717PubMedCrossRefGoogle Scholar
  85. Merlo A, de Quiros SB, de Santa-Maria IS, Pitiot AS, Balbin M, Astudillo A, Scola B, Aristegui M, Quer M, Suarez C, Chiara MD (2013) Identification of somatic VHL gene mutations in sporadic head and neck paragangliomas in association with activation of the HIF-1alpha/miR-210 signaling pathway. J Clin Endocrinol Metab 98:E1661–E1666PubMedCrossRefGoogle Scholar
  86. Michalowska I, Cwikla JB, Michalski W, Wyrwicz LS, Prejbisz A, Szperl M, Niec D, Neumann HP, Januszewicz A, Peczkowska M (2017) Growth rate of Paragangliomas related to germline mutations of the Sdhx genes. Endocr Pract 23:342–352PubMedCrossRefGoogle Scholar
  87. Mojet MH, Mills E, Duchen MR (1997) Hypoxia-induced catecholamine secretion in isolated newborn rat adrenal chromaffin cells is mimicked by inhibition of mitochondrial respiration. J Physiol 504(Pt 1):175–189PubMedPubMedCentralCrossRefGoogle Scholar
  88. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L et al (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460PubMedCrossRefGoogle Scholar
  89. Neal CS, Michael MZ, Rawlings LH, Van der Hoek MB, Gleadle JM (2010) The VHL-dependent regulation of microRNAs in renal cancer. BMC Med 8:64PubMedPubMedCentralCrossRefGoogle Scholar
  90. Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen M, Schiavi F, Falcioni M, Kwok P, Bauters C, Lampe K, Fischer M, Edelman E, Benn DE, Robinson BG, Wiegand S, Rasp G, Stuck BA, Hoffmann MM, Sullivan M, Sevilla MA, Weiss MM, Peczkowska M, Kubaszek A, Pigny P, Ward RL, Learoyd D, Croxson M, Zabolotny D, Yaremchuk S, Draf W, Muresan M, Lorenz RR, Knipping S, Strohm M, Dyckhoff G, Matthias C, Reisch N, Preuss SF, Esser D, Walter MA, Kaftan H, Stover T, Fottner C, Gorgulla H, Malekpour M, Zarandy MM, Schipper J, Brase C, Glien A, Kuhnemund M, Koscielny S, Schwerdtfeger P, Valimaki M, Szyfter W, Finckh U, Zerres K, Cascon A, Opocher G, Ridder GJ, Januszewicz A, Suarez C, Eng C (2009) Clinical predictors for germline mutations in head and neck paraganglioma patients: Cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res 69:3650–3656PubMedCrossRefGoogle Scholar
  91. NGS in PPGL Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, Welander J, Tops CM, Firth H, Dwight T, Ercolino T, Mannelli M, Opocher G, Clifton-Bligh R, Gimm O, Maher ER, Robledo M, Gimenez-Roqueplo AP, Dahia PL (2017) Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol 13:233–247CrossRefGoogle Scholar
  92. Oishi S, Sasaki M, Sato T (1994) Elevated immunoreactive endothelin levels in patients with pheochromocytoma. Am J Hypertens 7:717–722PubMedCrossRefGoogle Scholar
  93. Osinga TE, van der Horst-Schrivers AN, van Faassen M, Kerstens MN, Dullaart RP, Peters MA, van der Laan BF, de Bock GH, Links TP, Kema IP (2016) Dopamine concentration in blood platelets is elevated in patients with head and neck paragangliomas. Clin Chem Lab Med 54:1395–1401PubMedCrossRefGoogle Scholar
  94. Pamporaki C, Hamplova B, Peitzsch M, Prejbisz A, Beuschlein F, Timmers H, Fassnacht M, Klink B, Lodish M, Stratakis CA, Huebner A, Fliedner S, Robledo M, Sinnott RO, Januszewicz A, Pacak K, Eisenhofer G (2017) Characteristics of pediatric vs adult Pheochromocytomas and Paragangliomas. J Clin Endocrinol Metab 102:1122–1132PubMedPubMedCentralCrossRefGoogle Scholar
  95. Papaspyrou K, Mewes T, Rossmann H, Fottner C, Schneider-Raetzke B, Bartsch O, Schreckenberger M, Lackner KJ, Amedee RG, Mann WJ (2012) Head and neck paragangliomas: Report of 175 patients (1989-2010). Head Neck 34:632–637PubMedCrossRefGoogle Scholar
  96. Pawar A, Nanduri J, Yuan G, Khan SA, Wang N, Kumar GK, Prabhakar NR (2009) Reactive oxygen species-dependent endothelin signaling is required for augmented hypoxic sensory response of the neonatal carotid body by intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 296:R735–R742PubMedCrossRefGoogle Scholar
  97. Peitzsch M, Prejbisz A, Kroiss M, Beuschlein F, Arlt W, Januszewicz A, Siegert G, Eisenhofer G (2013) Analysis of plasma 3-methoxytyramine, normetanephrine and metanephrine by ultraperformance liquid chromatography-tandem mass spectrometry: Utility for diagnosis of dopamine-producing metastatic phaeochromocytoma. Ann Clin Biochem 50:147–155PubMedGoogle Scholar
  98. Piruat JI, Pintado CO, Ortega-Saenz P, Roche M, Lopez-Barneo J (2004) The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia. Mol Cell Biol 24:10933–10940PubMedPubMedCentralCrossRefGoogle Scholar
  99. Platero-Luengo A, Gonzalez-Granero S, Duran R, Diaz-Castro B, Piruat JI, Garcia-Verdugo JM, Pardal R, Lopez-Barneo J (2014) An O2-sensitive glomus cell-stem cell synapse induces carotid body growth in chronic hypoxia. Cell 156:291–303PubMedCrossRefGoogle Scholar
  100. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239PubMedCrossRefGoogle Scholar
  101. Prabhakar NR, Peng YJ, Kumar GK, Nanduri J, Di Giulio C, Lahiri S (2009) Long-term regulation of carotid body function: Acclimatization and adaptation--invited article. Adv Exp Med Biol 648:307–317PubMedPubMedCentralCrossRefGoogle Scholar
  102. Prabhakar NR, Semenza GL (2016) Regulation of carotid body oxygen sensing by hypoxia-inducible factors. Pflugers Arch 468:71–75PubMedCrossRefGoogle Scholar
  103. Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, Fourre S, Magnone V, Ricci JE, Pouyssegur J, Gounon P, Hofman P, Barbry P, Mari B (2011) miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ 18:465–478PubMedCrossRefGoogle Scholar
  104. Qin N, de Cubas AA, Garcia-Martin R, Richter S, Peitzsch M, Menschikowski M, Lenders JW, Timmers HJ, Mannelli M, Opocher G, Economopoulou M, Siegert G, Chavakis T, Pacak K, Robledo M, Eisenhofer G (2014) Opposing effects of HIF1alpha and HIF2alpha on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X. Int J Cancer 135:2054–2064PubMedCrossRefGoogle Scholar
  105. Rao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein F, Brugger C, Fliedner S, Langton K, Pamporaki C, Gudziol V, Stell A, Januszewicz A, Timmers H, Lenders JWM, Eisenhofer G (2017) Plasma methoxytyramine: Clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol 177:103–113PubMedPubMedCentralCrossRefGoogle Scholar
  106. Rao JU, Engelke UF, Rodenburg RJ, Wevers RA, Pacak K, Eisenhofer G, Qin N, Kusters B, Goudswaard AG, Lenders JW, Hermus AR, Mensenkamp AR, Kunst HP, Sweep FC, Timmers HJ (2013) Genotype-specific abnormalities in mitochondrial function associate with distinct profiles of energy metabolism and catecholamine content in pheochromocytoma and paraganglioma. Clin Cancer Res 19:3787–3795PubMedPubMedCentralCrossRefGoogle Scholar
  107. Rapizzi E, Ercolino T, Canu L, Giache V, Francalanci M, Pratesi C, Valeri A, Mannelli M (2012) Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers. Endocr Relat Cancer 19:261–269PubMedCrossRefGoogle Scholar
  108. Ravenna L, Salvatori L, Russo MA (2016) HIF3alpha: The little we know. FEBS J 283:993–1003PubMedCrossRefGoogle Scholar
  109. Remacha L, Comino-Mendez I, Richter S, Contreras L, Curras-Freixes M, Pita G, Leton R, Galarreta A, Torres-Perez R, Honrado E, Jimenez S, Maestre L, Moran S, Esteller M, Satrustegui J, Eisenhofer G, Robledo M, Cascon A (2017) Targeted exome sequencing of Krebs cycle genes reveals candidate cancer predisposing mutations in pheochromocytomas and paragangliomas. Clin Cancer Res (in press)Google Scholar
  110. Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, de Cubas AA, Schiavi F, Rao JU, Beuschlein F, Quinkler M, Timmers HJ, Opocher G, Mannelli M, Pacak K, Robledo M, Eisenhofer G (2014) Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab 99:3903–3911PubMedPubMedCentralCrossRefGoogle Scholar
  111. Richter S, Qin N, Pacak K, Eisenhofer G (2013) Role of hypoxia and HIF2alpha in development of the sympathoadrenal cell lineage and chromaffin cell tumors with distinct catecholamine phenotypic features. Adv Pharmacol 68:285–317PubMedPubMedCentralCrossRefGoogle Scholar
  112. Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER (2010) Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 31:41–51PubMedCrossRefGoogle Scholar
  113. Saldana MJ, Salem LE, Travezan R (1973) High altitude hypoxia and chemodectomas. Hum Pathol 4:251–263PubMedCrossRefGoogle Scholar
  114. Santana MM, Chung KF, Vukicevic V, Rosmaninho-Salgado J, Kanczkowski W, Cortez V, Hackmann K, Bastos CA, Mota A, Schrock E, Bornstein SR, Cavadas C, Ehrhart-Bornstein M (2012) Isolation, characterization, and differentiation of progenitor cells from human adult adrenal medulla. Stem Cells Transl Med 1:783–791PubMedPubMedCentralCrossRefGoogle Scholar
  115. Schiavi F, Boedeker CC, Bausch B, Peczkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forrer F, Valimaki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willet-Brozick JE, Baysal BE, Januszewicz A, Eng C, Opocher G, Neumann HP, European-American Paraganglioma Study G (2005) Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA 294:2057–2063PubMedCrossRefGoogle Scholar
  116. Schulte KM, Talat N, Galata G, Aylwin S, Izatt L, Eisenhofer G, Barthel A, Bornstein SR (2014) Genetics and the clinical approach to paragangliomas. Horm Metab Res 46:964–973PubMedCrossRefGoogle Scholar
  117. Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, Calabrese F, Laudiero G, Esposito F, Landriscina M, Defilippi P, Bernardi P, Rasola A (2013) The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab 17:988–999PubMedPubMedCentralCrossRefGoogle Scholar
  118. Shankavaram U, Fliedner SM, Elkahloun AG, Barb JJ, Munson PJ, Huynh TT, Matro JC, Turkova H, Linehan WM, Timmers HJ, Tischler AS, Powers JF, de Krijger R, Baysal BE, Takacova M, Pastorekova S, Gius D, Lehnert H, Camphausen K, Pacak K (2013) Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas. Neoplasia 15:435–447PubMedPubMedCentralCrossRefGoogle Scholar
  119. Slingo ME, Turner PJ, Christian HC, Buckler KJ, Robbins PA (2014) The von Hippel-Lindau Chuvash mutation in mice causes carotid-body hyperplasia and enhanced ventilatory sensitivity to hypoxia. J Appl Physiol (1985) 116:885–892CrossRefGoogle Scholar
  120. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A (2002) Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1alpha in ovarian carcinoma cells. J Biol Chem 277:27850–27855PubMedCrossRefGoogle Scholar
  121. Stenman A, Welander J, Gustavsson I, Brunaud L, Backdahl M, Soderkvist P, Gimm O, Juhlin CC, Larsson C (2016) HRAS mutation prevalence and associated expression patterns in pheochromocytoma. Genes Chromosomes Cancer 55:452–459PubMedPubMedCentralCrossRefGoogle Scholar
  122. Streeten DH, Anderson GH Jr (1996) Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens 9:760–769PubMedCrossRefGoogle Scholar
  123. Timmers HJ, Pacak K, Huynh TT, Abu-Asab M, Tsokos M, Merino MJ, Baysal BE, Adams KT, Eisenhofer G (2008) Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. J Clin Endocrinol Metab 93:4826–4832PubMedPubMedCentralCrossRefGoogle Scholar
  124. Tischler AS (2002) Chromaffin cells as models of endocrine cells and neurons. Ann N Y Acad Sci 971:366–370PubMedCrossRefGoogle Scholar
  125. Tischler AS (2008) Pheochromocytoma and extra-adrenal paraganglioma: Updates. Arch Pathol Lab Med 132:1272–1284PubMedGoogle Scholar
  126. Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, Prasad ML, Ocal IT, Rao S, Aronin N, Barontini M, Bruder J, Reddick RL, Chen Y, Aguiar RC, Dahia PL (2016) Recurrent mutations of chromatin-remodeling genes and kinase receptors in Pheochromocytomas and Paragangliomas. Clin Cancer Res 22:2301–2310PubMedCrossRefGoogle Scholar
  127. Tory K, Brauch H, Linehan M, Barba D, Oldfield E, Filling-Katz M, Seizinger B, Nakamura Y, White R, Marshall FF, Lerman MI, Zbar B (1989) Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst 81:1097–1101PubMedCrossRefGoogle Scholar
  128. Tsang VH, Dwight T, Benn DE, Meyer-Rochow GY, Gill AJ, Sywak M, Sidhu S, Veivers D, Sue CM, Robinson BG, Clifton-Bligh RJ, Parker NR (2014) Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours. Endocr Relat Cancer 21:415–426PubMedCrossRefGoogle Scholar
  129. Turkova H, Prodanov T, Maly M, Martucci V, Adams K, Widimsky J Jr, Chen CC, Ling A, Kebebew E, Stratakis CA, Fojo T, Pacak K (2016) Characteristics and outcomes of metastatic Sdhb and sporadic Pheochromocytoma/Paraganglioma: An National Institutes of Health study. Endocr Pract 22:302–314PubMedCrossRefGoogle Scholar
  130. van Duinen N, Steenvoorden D, Kema IP, Jansen JC, Vriends AH, Bayley JP, Smit JW, Romijn JA, Corssmit EP (2010) Increased urinary excretion of 3-methoxytyramine in patients with head and neck paragangliomas. J Clin Endocrinol Metab 95:209–214PubMedCrossRefGoogle Scholar
  131. Watanabe K, Hiraki H, Hasegawa H, Tanigawa T, Emura I, Honma K, Shibuya H, Fukuda T, Suzuki T (1997) Immunohistochemical localization of endothelin-1, endothelin-3 and endothelin receptors in human pheochromocytoma and paraganglioma. Pathol Int 47:540–546PubMedCrossRefGoogle Scholar
  132. 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 21:495–504PubMedCrossRefGoogle Scholar
  133. Yang C, Hong CS, Prchal JT, Balint MT, Pacak K, Zhuang Z (2015) Somatic mosaicism of EPAS1 mutations in the syndrome of paraganglioma and somatostatinoma associated with polycythemia. Hum Genome Var 2:15053PubMedPubMedCentralCrossRefGoogle Scholar
  134. 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 367:922–930PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Stephanie M. J. Fliedner
    • 1
  • Georg Brabant
    • 1
  • Hendrik Lehnert
    • 1
  1. 1.Medical Department 1University Medical Center Schleswig-HolsteinLübeckGermany

Personalised recommendations