Pheochromocytomas: From Genetic Diversity to New Paradigms

Abstract

Pheochromocytomas and paragangliomas are catecholamine-secreting tumors of neural crest origin caused by germline mutations in at least six distinct genes. This genetic heterogeneity has provided a rich source for both the discovery and functional characterization of new tumor-related genes. However, the genetic repertoire of these tumors is still not fully known, and current evidence points to the existence of additional pheochromocytoma susceptibility genes. Here, the unique contributions of three hereditary models of pheochromocytoma that can advance our knowledge of the disease pathogenesis are presented. The first model, loss of succinate dehydrogenase (SDH) function, illustrates how SDHB, C, or D mutations, components of the energy metabolism pathway, serve as a unique system to explore the pervasive metabolic shift of cancer cells towards glycolysis as a source of energy (also known as the Warburg effect) in contrast to the characteristic oxidative phosphorylation of normal cells. In the second model, mechanisms of tumorigenesis distinct from classical pheochromocytoma susceptibility genes are discussed in the context of a novel putative suppressor of neural crest-derived tumors, the KIF1Bβ gene. Finally, NF1 loss is highlighted as a valuable study model to investigate the cell lineage selectivity of the Egln3-mediated developmental apoptotic defect of chromaffin precursor cells. Results from these studies may offer clues to understand the tissue specificity of hereditary pheochromocytoma syndromes. These distinct hereditary disease models illustrate how genetic-driven progress has the potential to narrow current gaps in our knowledge of pheochromocytoma and paraganglioma pathogenesis.

Key words

adrenal medulla - adrenal tumor - pheochromocytoma - paraganglioma - tumor suppressor gene - hereditary cancer syndromes

References

• 1 Bravo EL. Pheochromocytoma.  Cardiol Rev. 2002;  10 44-50
• 2 Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germline mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.  Nature. 1993;  363 458-460
• 3 Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt M-L, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Weng Y, Duan DR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov I, Cohen D, Chinault CA, Maher ER, Linehan WM, Zbar B, Lerman MI. Identification of the von Hippel-Lindau disease tumor suppressor gene.  Science. 1993;  260 1317-1320
• 4 Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O’Connell P. Deletions and translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.  Cell. 1990;  62 187-192
• 5 Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.  Am J Hum Genet. 2001;  69 49-54
• 6 Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3.  Nat Genet. 2000;  26 268-270
• 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, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.  Science. 2000;  287 848-851
• 8 Dahia PLM, Ross K, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F Jr, Dluhy R, Sosa JA, IT O, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SPA, Nosé V, Li C, Stiles CD. A HIF1a regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.  PLoS Genet. 2005;  1 e8
• 9 Eisenhofer G, Siegert G, Kotzerke J, Bornstein SR, Pacak K. Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas.  Horm Metab Res. 2008;  40 329-337
• 10 Dahia PLM, Hao K, Rogus J, Colin C, Pujana MAG, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SPA, Stiles CD. Consortium ftFP . Novel pheochromocytoma susceptibility loci identified by integrative genomics.  Cancer Res. 2005;  65 9651-9658
• 11 Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update.  Nat Rev Cancer. 2005;  5 857-866
• 12 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Van Kien PK, Corvol P, Plouin PF, Jeunemaitre X. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.  Cancer Res. 2003;  63 5615-5621
• 13 Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas.  J Clin Endocrinol Metab. 2007;  92 3822-3828
• 14 Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.  Am J Hum Genet. 2001;  69 1186-1197
• 15 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.  J Clin Endocrinol Metab. 2002;  87 4771-4774
• 16 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. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.  Hum Mol Genet. 2005;  14 2231-2239
• 17 Selak MA, Armour SM, Mackenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.  Cancer Cell. 2005;  7 77-85
• 18 Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin  Jr  WG, Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer.  Cancer Cell. 2005;  8 155-167
• 19 Ishii T, Yasuda K, Akatsuka A, Hino O, Hartman PS, Ishii N. A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis.  Cancer Res. 2005;  65 203-209
• 20 Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT. 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. 2008;  28 718-731
• 21 Smith EH, Janknecht R, Maher  3rd  LJ. Succinate inhibition of {alpha}-ketoglutarate-dependent enzymes in a yeast model of paraganglioma.  Hum Mol Genet. 2007;  16 3136-3148
• 22 Cervera AM, Apostolova N, Crespo FL, Mata M, MacCreath KJ. Cells silenced for SDHB expression display characteristic features of the tumor phenotype.  Cancer Res. 2008;  68 4058-4067
• 23 Guo J, Lemire BD. The ubiquinone-binding site of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase is a source of superoxide.  J Biol Chem. 2003;  278 47629-47635
• 24 Piruat JI, Pintado CO, Ortega-Saenz P, Roche M, Lopez-Barneo J. 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. 2004;  24 10933-10940
• 25 Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW, Pacak K. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma.  J Clin Oncol. 2007;  25 2262-2269
• 26 Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment.  Oncogene. 2006;  25 4633-4646
• 27 Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.  Cancer Cell. 2006;  9 425-434
• 28 Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.  Cancer Cell. 2007;  11 37-51
• 29 Kondo K, Kim WY, Lechpammer M, Kaelin Jr WG. Inhibition of HIF2alpha Is Sufficient to Suppress pVHL-Defective Tumor Growth.  PLoS Biol. 2003;  1 E83
• 30 Kondo K, Klco J, Nakamura E, Lechpammer M, William G, Kaelin  Jr  WG. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.  Cancer Cell. 2002;  1 237-246
• 31 Eisenhofer G, Huynh T-T, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein D S, Elkahloun AG. 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
• 32 Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF1- to the phenotype of VHL loss in renal cell carcinoma.  Cancer Cell. 2002;  1 247-255
• 33 Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.  Cell Metab. 2006;  3 187-197
• 34 Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia.  Cell Metab. 2006;  3 177-185
• 35 Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation.  Cancer Cell. 2007;  12 108-113
• 36 Kim JW, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.  Mol Cell Biol. 2007;  27 7381-7393
• 37 Korpershoek E, Van Nederveen FH, Dannenberg H, Petri BJ, Komminoth P, Perren A, Lenders JW, Verhofstad AA, De Herder WW, De Krijger RR, Dinjens WN. Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience.  Ann N Y Acad Sci. 2006;  1073 138-148
• 38 Maris JM, Weiss MJ, Mosse Y, Hii G, Guo C, White PS, Hogarty MD, Mirensky T, Brodeur GM, Rebbeck TR, Urbanek M, Shusterman S. Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.  Cancer Res. 2002;  62 6651-6658
• 39 Gimenez-Roqueplo AP, Burnichon N, Amar L, Favier J, Jeunemaitre X, Plouin PF. Recent advances in the genetics of phaeochromocytoma and functional paraganglioma.  Clin Exp Pharmacol Physiol. 2008;  35 376-379
• 40 Bornstein SR, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma: increasing importance for clinical decision making.  Ann N Y Acad Sci. 2006;  1073 94-103
• 41 Bausch B, Boedeker CC, Berlis A, Brink I, Cybulla M, Walz MK, Januszewicz A, Letizia C, Opocher G, Eng C, Neumann HP. Genetic and clinical investigation of pheochromocytoma: a 22-year experience, from Freiburg, Germany to international effort.  Ann N Y Acad Sci. 2006;  1073 122-137
• 42 Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, Feunteun J, Pouyssegur J, Richard S, Gardie B. PHD2 mutation and congenital erythrocytosis with paraganglioma.  N Engl J Med. 2008;  359 2685-2692
• 43 Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin Jr WG. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor.  Genes Dev. 2008;  22 884-893
• 44 Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa N. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.  Cell. 2001;  105 587-597
• 45 Benn DE, Dwight T, Richardson AL, Delbridge L, Bambach CP, Stowasser M, Gordon RD, Marsh DJ, Robinson BG. Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.  Cancer Res. 2000;  60 7048-7051
• 46 Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH, Leteurtre E, Cao CD, Cardot-Bauters C, Pigny P, Dahia PL. A germline mutation of the KIF1Bbeta gene on 1p36 in a family with neural and nonneural tumors.  Hum Genet. 2008; 
• 47 Munirajan AK, Ando K, Mukai A, Takahashi M, Suenaga Y, Ohira M, Koda T, Hirota T, Ozaki T, Nakagawara A. KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death.  J Biol Chem. 2008;  283 24426-24434
• 48 Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.  Nature. 2007;  446 758-764
• 49 Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen.  2008;  451 335-339
• 50 Mannelli M, Simi L, Gagliano MS, Opocher G, Ercolino T, Becherini L, Parenti G. Genetics and biology of pheochromocytoma.  Exp Clin Endocrinol Diabetes. 2007;  115 160-165
• 51 Walther MM, Herring J, Enquist E, Keiser HR, Linehan WM. von Recklinghausen's disease and pheochromocytomas.  J Urol. 1999;  162 1582-1586
• 52 Vanharanta S, Buchta M, MacWhinney SR, Virta SK, Peczkowska M, Morrison CD, Lehtonen R, Januszewicz A, Jarvinen H, Juhola M, Mecklin JP, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HP, Eng C. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.  Am J Hum Genet. 2004;  74 153-159
• 53 Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER. Germline SDHB mutations and familial renal cell carcinoma.  J Natl Cancer Inst. 2008;  100 1260-1262
• 54 MacWhinney SR, Pasini B, Stratakis CA. The International Carney Triad Carney-Stratakis Syndrome Consortium . Familial Gastrointestinal Stromal Tumors and Germ-Line Mutations.  N Engl J Med. 2007;  357 1054-1056
• 55 Zbuk KM, Patocs A, Shealy A, Sylvester H, Miesfeldt S, Eng C. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma.  Nat Clin Pract Oncol. 2007;  4 608-612
• 56 Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of Pheochromocytoma/ Paraganglioma syndromes.  J Clin Endocrinol Metab. 2006;  91 827-836
• 57 Cascon A, Landa I, Lopez-Jimenez E, Diez-Hernandez A, Buchta M, Montero-Conde C, Leskela S, Leandro-Garcia LJ, Leton R, Rodriguez-Antona C, Eng C, Neumann HP, Robledo M. Molecular characterisation of a common SDHB deletion in paraganglioma patients.  J Med Genet. 2008;  45 233-238
• 58 Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.  Am J Hum Genet. 2008;  83 261-268
• 59 Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.  Genes Dev. 1994;  8 1019-1029
• 60 Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.  Nat Genet. 1994;  7 353-361
• 61 Vogel KS, Brannan CI, Jenkins NA, Copeland NG, Parada LF. Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.  Cell. 1995;  82 733-742
• 62 Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP, Nicholls LG, Ortega-Saenz P, Oster H, Wijeyekoon B, Sutherland AI, Grosfeld A, Aragones J, Schneider M, van Geyte K, Teixeira D, Diez-Juan A, Lopez-Barneo J, Channon KM, Maxwell PH, Pugh CW, Davies AM, Carmeliet P, Ratcliffe PJ. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice.  Mol Cell Biol. 2008;  28 3386-3400
• 63 Quartu M, Serra MP, Boi M, Ferretti MT, Lai ML, Del Fiacco M. Tissue distribution of Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human brainstem at fetal, neonatal and adult age.  Brain Res. 2007;  1173 36-52
• 64 Kim WY, Sharpless NE. VHL Inactivation: A New Road to Senescence.  Cancer Cell. 2008;  13 295-297
• 65 Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.  2007;  8 729-740
• 66 Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L, Grisanzio C, Signoretti S, Kaelin Jr WG. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400.  Nat Cell Biol. 2008;  10 361-369
• 67 Pasini B, MacWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.  Eur J Hum Genet. 2008;  16 79-88

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