Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Rethinking pheochromocytomas and paragangliomas from a genomic perspective

Subjects

Abstract

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Saldana MJ, Salem LE, Travezan R . High altitude hypoxia and chemodectomas. Hum Pathol 1973; 4: 251–263.

    CAS  PubMed  Google Scholar 

  2. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 1915–1942.

    CAS  PubMed  Google Scholar 

  3. Favier J, Amar L, Gimenez-Roqueplo A . Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol 2014; 11: 101–111.

    PubMed  Google Scholar 

  4. Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D et al. 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 2012; 48: 1739–1749.

    CAS  PubMed  Google Scholar 

  5. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003; 63: 5615–5621.

    CAS  PubMed  Google Scholar 

  6. Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 2007; 92: 3822–3828.

    CAS  PubMed  Google Scholar 

  7. Eng C, Crossey PA, Mulligan LM, Healey CS, Houghton C, Prowse A 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 1995; 32: 934–937.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Eng C, Mulligan LM . Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum Mutat 1997; 9: 97–109.

    CAS  PubMed  Google Scholar 

  9. Griffiths DF, Williams GT, Williams ED . Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel-Lindau complex: two distinctive neuroendocrine syndromes. Q J Med 1987; 64: 769–782.

    CAS  PubMed  Google Scholar 

  10. Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TW, Wheeler DC, Ponder BA et al. Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. J Med Genet 1995; 32: 885–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kalff V, Shapiro B, Lloyd R, Sisson JC, Holland K, Nakajo M et al. The spectrum of pheochromocytoma in hypertensive patients with neurofibromatosis. Arch Intern Med 1982; 142: 2092–2098.

    CAS  PubMed  Google Scholar 

  12. DeAngelis LM, Kelleher MB, Post KD, Fetell MR . Multiple paragangliomas in neurofibromatosis: a new neuroendocrine neoplasia. Neurology 1987; 37: 129–133.

    CAS  PubMed  Google Scholar 

  13. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848–851.

    CAS  PubMed  Google Scholar 

  14. Niemann S, Muller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26: 268–270.

    CAS  PubMed  Google Scholar 

  15. Milunsky JM, Maher TA, Michels VV, Milunsky A . Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet 2001; 100: 311–314.

    CAS  PubMed  Google Scholar 

  16. Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet 2001; 357: 1181–1182.

    CAS  PubMed  Google Scholar 

  17. Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010; 19: 3011–3020.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 2010; 11: 366–372.

    CAS  PubMed  Google Scholar 

  19. Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

    CAS  PubMed  Google Scholar 

  20. Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2011; 108: 314–318.

    CAS  PubMed  Google Scholar 

  21. Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100: 1260–1262.

    CAS  PubMed  Google Scholar 

  22. Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010; 42: 229–233.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Perez L, King EE et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA 2010; 304: 2611–2619.

    CAS  PubMed  Google Scholar 

  24. Burnichon N, Lepoutre-Lussey C, Laffaire J, Gadessaud N, Molinie V, Hernigou A et al. A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma. Eur J Endocrinol 2011; 164: 141–145.

    CAS  PubMed  Google Scholar 

  25. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011; 43: 663–667.

    CAS  PubMed  Google Scholar 

  26. Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 2012; 18: 2828–2837.

    CAS  PubMed  Google Scholar 

  27. Favier J, Buffet A, Gimenez-Roqueplo AP . HIF2A mutations in paraganglioma with polycythemia. N Engl J Med 2012; 367: 2161; (author reply 2161–2162).

    CAS  PubMed  Google Scholar 

  28. Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012; 367: 922–930.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Comino-Mendez I, de Cubas AA, Bernal C, Alvarez-Escola C, Sanchez-Malo C, Ramirez-Tortosa CL et al. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Hum Mol Genet 2013; 22: 2169–2176.

    CAS  PubMed  Google Scholar 

  30. Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013; 23: 739–752.

    CAS  PubMed  Google Scholar 

  31. Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA et al. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 2014. jc20141659.

  32. Crona J, Delgado Verdugo A, Maharjan R, Stalberg P, Granberg D, Hellman P et al. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J Clin Endocrinol Metab 2013; 98: E1266–E1271.

    CAS  PubMed  Google Scholar 

  33. Oudijk L, de Krijger RR, Rapa I, Beuschlein F, de Cubas AA, Dei Tos AP et al. H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: data from a multi-institutional series. J Clin Endocrinol Metab 2014; 99: E1376–E1380.

    CAS  PubMed  Google Scholar 

  34. Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH, Leteurtre E et al. A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum Genet 2008; 124: 279–285.

    CAS  PubMed  Google Scholar 

  35. Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 2008; 22: 884–893.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 2008; 359: 2685–2692.

    CAS  PubMed  Google Scholar 

  37. Yang C, Zhuang Z, Fliedner SM, Shankavaram U, Sun MG, Bullova P et al. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J Mol Med (Berl) 2014; 93: 93–104.

    Google Scholar 

  38. Cascon A, Comino-Mendez I, Curras-Freixes M, de Cubas AA, Contreras L, Richter S et al. Whole-Exome Sequencing Identifies MDH2 as a New Familial Paraganglioma Gene. J Natl Cancer Inst 2015; 107.

  39. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab 2006; 91: 4505–4509.

    CAS  PubMed  Google Scholar 

  40. Klein RD, Jin L, Rumilla K, Young Jr WF, Lloyd RV . Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. Diagn Mol Pathol 2008; 17: 94–100.

    CAS  PubMed  Google Scholar 

  41. Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014; 23: 2440–2446.

    CAS  PubMed  Google Scholar 

  42. Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM et al. 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 2004; 11: 897–911.

    CAS  PubMed  Google Scholar 

  43. Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: 72–80.

    CAS  PubMed  Google Scholar 

  44. Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 2011; 20: 3974–3985.

    CAS  PubMed  Google Scholar 

  45. Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 2009; 4: e7094.

    PubMed  PubMed Central  Google Scholar 

  46. Burnichon N, Buffet A, Parfait B, Letouze E, Laurendeau I, Loriot C et al. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet 2012; 21: 5397–5405.

    CAS  PubMed  Google Scholar 

  47. Robinson CM, Ohh M . The multifaceted von Hippel-Lindau tumour suppressor protein. FEBS Lett 2014; 588: 2704–2711.

    CAS  PubMed  Google Scholar 

  48. Favier J, Gimenez-Roqueplo AP . Pheochromocytomas: the (pseudo)-hypoxia hypothesis. Best Pract Res Clin Endocrinol Metab 2010; 24: 957–968.

    CAS  PubMed  Google Scholar 

  49. Loriot C, Burnichon N, Gadessaud N, Vescovo L, Amar L, Libe R et al. Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. J Clin Endocrinol Metab 2012; 97: E954–E962.

    CAS  PubMed  Google Scholar 

  50. Szabo PM, Pinter M, Szabo DR, Zsippai A, Patocs A, Falus A et al. Integrative analysis of neuroblastoma and pheochromocytoma genomics data. BMC Med Genomics 2012; 5: 48.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E et al. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun 2015; 6: 6044.

    CAS  PubMed  Google Scholar 

  52. Negrini S, Gorgoulis VG, Halazonetis TD . Genomic instability–an evolving hallmark of cancer. Nat Rev Mol Cell Biol 2010; 11: 220–228.

    CAS  PubMed  Google Scholar 

  53. Khosla S, Patel VM, Hay ID, Schaid DJ, Grant CS, van Heerden JA et al. Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas. J Clin Invest 1991; 87: 1691–1699.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Vargas MP, Zhuang Z, Wang C, Vortmeyer A, Linehan WM, Merino MJ . Loss of heterozygosity on the short arm of chromosomes 1 and 3 in sporadic pheochromocytoma and extra-adrenal paraganglioma. Hum Pathol 1997; 28: 411–415.

    CAS  PubMed  Google Scholar 

  55. Aarts M, Dannenberg H, deLeeuw RJ, van Nederveen FH, Verhofstad AA, Lenders JW et al. Microarray-based CGH of sporadic and syndrome-related pheochromocytomas using a 0.1-0.2Mb bacterial artificial chromosome array spanning chromosome arm 1p. Genes Chromosomes Cancer 2006; 45: 83–93.

    CAS  PubMed  Google Scholar 

  56. Dannenberg H, Speel EJ, Zhao J, Saremaslani P, van Der Harst E, Roth J et al. Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas. Am J Pathol 2000; 157: 353–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Edstrom E, Mahlamaki E, Nord B, Kjellman M, Karhu R, Hoog A et al. Comparative genomic hybridization reveals frequent losses of chromosomes 1p and 3q in pheochromocytomas and abdominal paragangliomas, suggesting a common genetic etiology. Am J Pathol 2000; 156: 651–659.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Dannenberg H, de Krijger RR, Zhao J, Speel EJ, Saremaslani P, Dinjens WN et al. Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization. Am J Pathol 2001; 158: 1937–1942.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. August C, August K, Schroeder S, Bahn H, Hinze R, Baba HA et al. CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas. Mod Pathol 2004; 17: 1119–1128.

    CAS  PubMed  Google Scholar 

  60. Cascon A, Ruiz-Llorente S, Rodriguez-Perales S, Honrado E, Martinez-Ramirez A, Leton R et al. A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma. Genes Chromosomes Cancer 2005; 42: 260–268.

    CAS  PubMed  Google Scholar 

  61. Jarbo C, Buckley PG, Piotrowski A, Mantripragada KK, Benetkiewicz M, Diaz de Stahl T et al. Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH. Int J Cancer 2006; 118: 1159–1164.

    CAS  PubMed  Google Scholar 

  62. van Nederveen FH, Korpershoek E, deLeeuw RJ, Verhofstad AA, Lenders JW, Dinjens WN et al. Array-comparative genomic hybridization in sporadic benign pheochromocytomas. Endocr Relat Cancer 2009; 16: 505–513.

    CAS  PubMed  Google Scholar 

  63. Sandgren J, Diaz de Stahl T, Andersson R, Menzel U, Piotrowski A, Nord H et al. Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis. Endocr Relat Cancer 2010; 17: 561–579.

    CAS  PubMed  Google Scholar 

  64. Welander J, Larsson C, Backdahl M, Hareni N, Sivler T, Brauckhoff M et al. Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Hum Mol Genet 2012; 21: 5406–5416.

    CAS  PubMed  Google Scholar 

  65. Flynn A, Benn D, Clifton-Bligh R, Robinson B, Trainer AH, James P et al. The genomic landscape of phaeochromocytoma. J Pathol 2014; 236: 78–89.

    Google Scholar 

  66. Powers JF, Tischler AS, Mohammed M, Naeem R . Microarray-based comparative genomic hybridization of pheochromocytoma cell lines from neurofibromatosis knockout mice reveals genetic alterations similar to those in human pheochromocytomas. Cancer Genet Cytogenet 2005; 159: 27–31.

    CAS  PubMed  Google Scholar 

  67. Bagchi A, Mills AA . The quest for the 1p36 tumor suppressor. Cancer Res 2008; 68: 2551–2556.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kok K, Naylor SL, Buys CH . Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res 1997; 71: 27–92.

    CAS  PubMed  Google Scholar 

  69. Petri BJ, Speel EJ, Korpershoek E, Claessen SM, van Nederveen FH, Giesen V et al. Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas. Mod Pathol 2008; 21: 407–413.

    CAS  PubMed  Google Scholar 

  70. Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 2014; 46: 607–612.

    CAS  PubMed  Google Scholar 

  71. Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 2012; 483: 589–593.

    CAS  PubMed  Google Scholar 

  72. Kupka S, Haack B, Zdichavsky M, Mlinar T, Kienzle C, Bock T et al. Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel. J Cancer Res Clin Oncol 2008; 134: 463–471.

    CAS  PubMed  Google Scholar 

  73. Garraway LA, Lander ES . Lessons from the cancer genome. Cell 2013; 153: 17–37.

    CAS  PubMed  Google Scholar 

  74. Wheeler DA, Wang L . From human genome to cancer genome: the first decade. Genome Res 2013; 23: 1054–1062.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 2012; 488: 100–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 2013; 45: 279–284.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014; 506: 445–450.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Stratton MR, Campbell PJ, Futreal PA . The cancer genome. Nature 2009; 458: 719–724.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D'Andrea K, Merrill S et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun 2015; 6: 6140.

    CAS  PubMed  Google Scholar 

  81. Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014; 46: 444–450.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482: 226–231.

    CAS  PubMed  Google Scholar 

  83. Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC et al. The genetic landscape of the childhood cancer medulloblastoma. Science 2011; 331: 435–439.

    CAS  PubMed  Google Scholar 

  84. Huether R, Dong L, Chen X, Wu G, Parker M, Wei L et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 2014; 5: 3630.

    PubMed  Google Scholar 

  85. Karpathakis A, Dibra H, Thirlwell C . Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer 2013; 20: R65–R82.

    CAS  PubMed  Google Scholar 

  86. Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 2010; 464: 999–1005.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Luca R, Averna M, Zalfa F, Vecchi M, Bianchi F, La Fata G et al. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation. EMBO Mol Med 2013; 5: 1523–1536.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Herfarth KK, Wick MR, Marshall HN, Gartner E, Lum S, Moley JF . Absence of TP53 alterations in pheochromocytomas and medullary thyroid carcinomas. Genes Chromosomes Cancer 1997; 20: 24–29.

    CAS  PubMed  Google Scholar 

  89. Geli J, Kiss N, Karimi M, Lee JJ, Backdahl M, Ekstrom TJ et al. Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas: association to malignant behavior. Clin Cancer Res 2008; 14: 2551–2559.

    CAS  PubMed  Google Scholar 

  90. Liu X, Newton RC, Scherle PA . Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med 2010; 16: 37–45.

    CAS  PubMed  Google Scholar 

  91. Blumenschein GR Jr., Mills GB, Gonzalez-Angulo AM . Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012; 30: 3287–3296.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505: 495–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W . Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet 2014; 46: 1160–1165.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Papathomas TG, Oudijk L, Zwarthoff EC, Post E, Duijkers FA, van Noesel MM et al. Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocr Relat Cancer 2014; 21: 653–661.

    CAS  PubMed  Google Scholar 

  95. Liu T, Brown TC, Juhlin CC, Andreasson A, Wang N, Backdahl M et al. The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors. Endocr Relat Cancer 2014; 21: 427–434.

    PubMed  PubMed Central  Google Scholar 

  96. Feinberg AP, Tycko B . The history of cancer epigenetics. Nat Rev Cancer 2004; 4: 143–153.

    CAS  PubMed  Google Scholar 

  97. Feinberg AP . The epigenetics of cancer etiology. Semin Cancer Biol 2004; 14: 427–432.

    CAS  PubMed  Google Scholar 

  98. Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 2013; 3: 648–657.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ et al. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med 2014; 6: 268ra177.

    PubMed  PubMed Central  Google Scholar 

  100. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 2012; 26: 1326–1338.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Morin A, Letouze E, Gimenez-Roqueplo AP, Favier J . Oncometabolites-driven tumorigenesis: From genetics to targeted therapy. Int J Cancer 2014; 135: 2237–2248.

    CAS  PubMed  Google Scholar 

  102. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17: 510–522.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y et al. CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res 2005; 65: 828–834.

    CAS  PubMed  Google Scholar 

  105. Abe M, Westermann F, Nakagawara A, Takato T, Schwab M, Ushijima T . Marked and independent prognostic significance of the CpG island methylator phenotype in neuroblastomas. Cancer Lett 2007; 247: 253–258.

    CAS  PubMed  Google Scholar 

  106. Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861–874.

    CAS  PubMed  Google Scholar 

  107. Adams BD, Kasinski AL, Slack FJ . Aberrant regulation and function of microRNAs in cancer. Curr Biol 2014; 24: R762–R776.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Igaz P, Igaz I, Nagy Z, Nyiro G, Szabo PM, Falus A et al. MicroRNAs in adrenal tumors: relevance for pathogenesis, diagnosis, and therapy. Cell Mol Life Sci 2015; 72: 417–428.

    CAS  PubMed  Google Scholar 

  109. Tombol Z, Eder K, Kovacs A, Szabo PM, Kulka J, Liko I et al. MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas. Mod Pathol 2010; 23: 1583–1595.

    PubMed  Google Scholar 

  110. Meyer-Rochow GY, Jackson NE, Conaglen JV, Whittle DE, Kunnimalaiyaan M, Chen H et al. MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets. Endocr Relat Cancer 2010; 17: 835–846.

    CAS  PubMed  Google Scholar 

  111. Patterson E, Webb R, Weisbrod A, Bian B, He M, Zhang L et al. The microRNA expression changes associated with malignancy and SDHB mutation in pheochromocytoma. Endocr Relat Cancer 2012; 19: 157–166.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. de Cubas AA, Leandro-Garcia LJ, Schiavi F, Mancikova V, Comino-Mendez I, Inglada-Perez L et al. Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. Endocr Relat Cancer 2013; 20: 477–493.

    CAS  PubMed  Google Scholar 

  113. Zhang QH, Sun HM, Zheng RZ, Li YC, Zhang Q, Cheng P et al. Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. Gene 2013; 527: 26–32.

    CAS  PubMed  Google Scholar 

  114. Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA 2009; 106: 1814–1819.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Weeraratne SD, Amani V, Teider N, Pierre-Francois J, Winter D, Kye MJ et al. Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol 2012; 123: 539–552.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK et al. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 2009; 35: 856–867.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Qin Q, Furong W, Baosheng L . Multiple functions of hypoxia-regulated miR-210 in cancer. J Exp Clin Cancer Res 2014; 33: 50.

    PubMed  PubMed Central  Google Scholar 

  118. Agrawal R, Pandey P, Jha P, Dwivedi V, Sarkar C, Kulshreshtha R . Hypoxic signature of microRNAs in glioblastoma: insights from small RNA deep sequencing. BMC Genomics 2014; 15: 686.

    PubMed  PubMed Central  Google Scholar 

  119. da Rocha ST, Edwards CA, Ito M, Ogata T, Ferguson-Smith AC . Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends Genet 2008; 24: 306–316.

    PubMed  Google Scholar 

  120. Astuti D, Latif F, Wagner K, Gentle D, Cooper WN, Catchpoole D et al. Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour. Br J Cancer 2005; 92: 1574–1580.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Laddha SV, Nayak S, Paul D, Reddy R, Sharma C, Jha P et al. Genome-wide analysis reveals downregulation of miR-379/miR-656 cluster in human cancers. Biol Direct 2013; 8: 10.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Modali SD, Parekh VI, Kebebew E, Agarwal SK . Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors. Mol Endocrinol 2015. me20141304.

  123. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343: 1350–1354.

    CAS  PubMed  Google Scholar 

  124. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003.

    CAS  PubMed  Google Scholar 

  125. Hadoux J, Favier J, Scoazec JY, Leboulleux S, Al Ghuzlan A, Caramella C et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 2014; 135: 2711–2720.

    CAS  PubMed  Google Scholar 

  126. Cancer Genome Atlas Research N Weinstein JN Collisson EA Mills GB Shaw KR Ozenberger BA et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45: 1113–1120.

    Google Scholar 

  127. Hanahan D, Coussens LM . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–322.

    CAS  PubMed  Google Scholar 

  128. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40: 499–507.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Agence Nationale de la Recherche (ANR-2011-JCJC-00701 MODEOMAPP), the European Union Seventh Framework Program FP7/2007-2013 (grant agreement no. 259735), the Programme Hospitalier de Recherche Clinique (COMETE 3 AOM 06 179) and the Plan Cancer Action n°3.2 2009-2013 (AAP Épigénétique et Cancer 2013, U970-C13089KS-INSERM PLAN CANCER) for financial support. CL-L received funding from the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégré sur le Cancer - SIRIC). We apologize to researchers in the field whose contributions were not cited because of space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J Favier.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Castro-Vega, L., Lepoutre-Lussey, C., Gimenez-Roqueplo, AP. et al. Rethinking pheochromocytomas and paragangliomas from a genomic perspective. Oncogene 35, 1080–1089 (2016). https://doi.org/10.1038/onc.2015.172

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.172

This article is cited by

Search

Quick links