Download PDF
Horm Metab Res 2005; 37(6): 384-390
DOI: 10.1055/s-2005-870156
Review
© Georg Thieme Verlag KG Stuttgart · New York

New Insights in the Genetics of Adrenocortical Tumors, Pheochromocytomas and Paragangliomas

J.  Bertherat1 , A.-P.  Gimenez-Roqueplo2
  • 1Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V and INSERM U567 and CNRS UMR8104, Institut Cochin
  • 2Département de Génétique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris V and INSERM U36, Collège de France, Paris, France with the support of PHRC grant AOM02068 and grants from INSERM and the Ministère Délégué à la Recherche et aux Nouvelles Technologies for the COMETE network and GIS-Institut des Maladies Rares for the PGL.NET network, Carney Complex network (CCN) and European Network for the Study of Adrenal Tumors (ENSAT)
Further Information

Publication History

Received 10 September 2004

Accepted after revision 28 October 2004

Publication Date:
07 July 2005 (online)

Also available at
    Permissions and Reprints

Abstract

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors.The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing

Key words

Adrenocortical tumor - Li-Fraumeni syndrome - Beckwith-Wiedemann syndrome - Multiple endocrine neoplasia type 1 - Carney complex - Paraganglioma - Pheochromocytoma

References

  • 1 Luton J P, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat M H, Louvel A, Chapuis Y, Blondeau P, Bricaire H. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy.  N Engl J Med.. 1990;  322 1195-201
    PubMedGoogle Scholar
  • 2 Hisada M, Garber J E, Fung C Y, Fraumeni J F Jr, Li F P. Multiple primary cancers in families with Li-Fraumeni syndrome.  J Natl Cancer Inst. 1998;  90 606-611
    CrossrefPubMedGoogle Scholar
  • 3 Varley J M, McGown G, Thorncroft M, James L A, Margison G P, Forster G, Evans D G, Harris M, Kelsey A M, Birch J M. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.  Am J Hum Genet. 1999;  65 995-1006
    CrossrefPubMedGoogle Scholar
  • 4 Bell D W, Varley J M, Szydlo T E, Kang D H, Wahrer D C, Shannon K E, Lubratovich M, Verselis S J, Isselbacher K J, Fraumeni J F, Birch J M, Li F P, Garber J E, Haber D A. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.  Science. 1999;  286 2528-2531
    CrossrefPubMedGoogle Scholar
  • 5 Wagner J, Portwine C, Rabin K, Leclerc J M, Narod S A, Malkin D. High frequency of germline p53 mutations in childhood adrenocortical cancer.  J Natl Cancer Inst. 1994;  86 1707-1710
    CrossrefPubMedGoogle Scholar
  • 6 Ribeiro R C, Sandrini F, Figueiredo B, Zambetti G P, Michalkiewicz E, Lafferty A R, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis C A, Sandrini R. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.  Proc Natl Acad Sci USA. 2001;  98 9330-9335
    CrossrefPubMedGoogle Scholar
  • 7 Latronico A C, Pinto E M, Domenice S, Fragoso M C, Martin R M, Zerbini M C, Lucon A M, Mendonca B B. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 2001;  86 4970-4973
    PubMedGoogle Scholar
  • 8 DiGiammarino E L, Lee A S, Cadwell C, Zhang W, Bothner B, Ribeiro R C, Zambetti G, Kriwacki R W. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.  Nat Struct Biol. 2002;  9 12-16
    CrossrefPubMedGoogle Scholar
  • 9 Bertherat J, Gicquel C, Le Bouc Y, Bertagna X. Molecular genetics of adrenal tumours. In: John A H Wass, Stephen M Shalet (eds) Oxford textbook of Endocrinology and Diabetes. Oxford; Oxford University press 2002: 831-842
    Google Scholar
  • 10 Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos J M, Schlumberger M, Plouin P F, Luton J P, Le Bouc YB. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors.  Cancer Res. 2001;  61 6762-6767
    PubMedGoogle Scholar
  • 11 De Fraipont F, Le Moigne G, Defaye G, El Atifi M, Berger F, Houlgatte R, Gicquel C, Plouin P F, Bertagna X, Chabre O, Feige J J. Transcription profiling of benign and malignant adrenal tumors by cDNA macro-array analysis.  Endocr Res. 2002;  28 785-786
    CrossrefPubMedGoogle Scholar
  • 12 Giordano T J, Thomas D G, Kuick R, Lizyness M, Misek D E, Smith A L, Sanders D, Aljundi R T, Gauger P G, Thompson N W, Taylor J M, Hanash S M. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis.  Am J Pathol. 2003;  162 521-531
    CrossrefPubMedGoogle Scholar
  • 13 Bourdeau I, Antonini S R, Lacroix A, Kirschner L S, Matyakhina L, Lorang D, Libutti S K, Stratakis C A. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators.  Oncogene. 2004;  23 1575-1585
    CrossrefPubMedGoogle Scholar
  • 14 Thakker R V. Multiple endocrine neoplasia - syndromes of the twentieth century.  J Clin Endocrinol Metab. 1998;  83 2617-2620
    CrossrefPubMedGoogle Scholar
  • 15 Kjellman M, Roshani L, Teh B T, Kallioniemi O P, Hoog A, Gray S, Farnebo L O, Holst M, Backdahl M, Larsson C. Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.  J Clin Endocrinol Metab. 1999;  84 730-735
    CrossrefPubMedGoogle Scholar
  • 16 Schulte K M, Mengel M, Heinze M, Simon D, Scheuring S, Kohrer K, Roher H D. Complete sequencing and messenger ribonucleic acid expression analysis of the MEN I gene in adrenal cancer.  J Clin Endocrinol Metab. 2000;  85 441-448
    CrossrefPubMedGoogle Scholar
  • 17 Carney J A, Gordon H, Carpenter P C, Shenoy B V, Go V L. The complex of myxomas, spotty pigmentation, and endocrine overactivity.  Medicine (Baltimore). 1985;  64 270-283
    CrossrefPubMedGoogle Scholar
  • 18 Kirschner L S, Carney J A, Pack S D, Taymans S E, Giatzakis C, Cho Y S, Cho-Chung Y S, Stratakis C A. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.  Nat Genet. 2000;  26 89-92
    Google Scholar
  • 19 Kirschner L S, Sandrini F, Monbo J, Lin J P, Carney J A, Stratakis C A. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.  Hum Mol Genet. 2000;  9 3037-3046
    CrossrefPubMedGoogle Scholar
  • 20 Bertherat J. Protein kinase A in Carney Complex: a new example of cAMP pathway alteration in endocrine tumors.  Eur J Endocrinol. 2001;  144 209-211
    CrossrefPubMedGoogle Scholar
  • 21 Groussin L, Kirschner L S, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney J A, Luton J P, Bertagna X, Stratakis C A, Bertherat J. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.  Am J Hum Genet. 2002;  71 1433-1442
    CrossrefPubMedGoogle Scholar
  • 22 Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, Luton J P, Bertagna X, Bertherat J. Mutations of the PRKAR1A gene in Cushing’s syndrome due to sporadic primary pigmented nodular adrenocortical disease.  J Clin Endocrinol Metab. 2002;  87 4324-4329
    Google Scholar
  • 23 Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner L S, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis C A. Molecular and functional analysis of PRKAR1A and its locus (17q22 - 24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.  Cancer Res. 2003;  63 5308-5319
    PubMedGoogle Scholar
  • 24 Eng C, Crossey P A, Mulligan L M, Healey C S, Houghton C, Prowse A, Chew S L, Dahia P LM, O'Riordan J LH, Toledo SPA , Smith D P, Maher E R, Ponder B J. 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
    PubMedGoogle Scholar
  • 25 Brandi M L, Gagel R F, Angeli A, Bilezikian J P, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri R G, Libroia A, Lips C J, Lombardi G, Mannelli M, Pacini F, Ponder B A, Raue F, Skogseid B, Tamburrano G, Thakker R V, Thompson N W, Tomassetti P, Tonelli F, Wells S A Jr, Marx S J. Guidelines for diagnosis and therapy of MEN type 1 and type 2.  J Clin Endocrinol Metab. 2001;  86 5658-5671
    CrossrefPubMedGoogle Scholar
  • 26 Lonser R R, Glenn G M, Walther M, Chew E Y, Libutti S K, Linehan W M, Oldfield E H. von Hippel-Lindau disease.  Lancet. 2003;  361 2059-2067
    CrossrefPubMedGoogle Scholar
  • 27 Reynolds R M, Browning G G, Nawroz I, Campbell I W. Von Recklinghausen’s neurofibromatosis: neurofibromatosis type 1.  Lancet. 2003;  361 1552-1554
    CrossrefPubMedGoogle Scholar
  • 28 Dluhy R G. Pheochromocytoma-Death of an axiom.  N Engl J Med. 2002;  19 1486-1488
    PubMedGoogle Scholar
  • 29 Rao A B, Koeller K K, Adair C F. Paragangliomas of the head and neck: radiologic-pathologic correlation.  Radiographics. 1999;  19 1605-1632
    PubMedGoogle Scholar
  • 30 van der Mey A G, Maaswinkel-Mooy P D, Cornelisse C J, Schmidt P H, van de Kamp J J. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory.  Lancet. 1989;  2 1291-1294
    PubMedGoogle Scholar
  • 31 Baysal B E, Ferrell R E, Willett-Brozick J E, Lawrence E C, Myssiorek D, Bosch A, Van de Mey A, Taschner P EM, Rubinstein W S, Myers E N, Richard III C W, Cornelisse C J, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.  Science. 2000;  287 848-851
    CrossrefPubMedGoogle Scholar
  • 32 Astuti D, Latif F, Dallol A, Dahia P LM, Douglas F, George E, Sköldberg F, Husebye E S, Eng C, Maher E R. 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
    CrossrefPubMedGoogle Scholar
  • 33 Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3.  Nat Genet. 2000;  26 268-270
    CrossrefPubMedGoogle Scholar
  • 34 Baysal B E. Hereditary paraganglioma targets diverse paraganglia.  J Med Genet. 2002;  39 617-622
    CrossrefPubMedGoogle Scholar
  • 35 Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.  Nat Genet. 1995;  11 144-149
    PubMedGoogle Scholar
  • 36 Tomlinson I P, Alam N A, Rowan A J, Barclay E, Jaeger E E, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance R R, Olpin S, Bevan S, Barker K, Hearle N, Houlston R S, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen L A;. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.  Nat Genet. 2002;  30 406-410
    CrossrefPubMedGoogle Scholar
  • 37 Rustin P. Mitochondria, from cell death to proliferation.  Nature Genet. 2002;  30 352-353
    CrossrefPubMedGoogle Scholar
  • 38 Eng C, Kiuru M, Fernandez M J, Aaltonen L A. A role for mitochondrial enzymes in inherited neoplasia and beyond.  Nat Rev Cancer. 2003;  3 193-202
    CrossrefPubMedGoogle Scholar
  • 39 Gimenez-Roqueplo A P, Favier J, Rustin P, Mourad J J, Plouin P F, 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
    CrossrefPubMedGoogle Scholar
  • 40 Gimenez-Roqueplo A P, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin P F, Rotig A, Jeunemaitre X. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.  J Clin Endocrinol Metab. 2002;  87 4771-4774
    CrossrefPubMedGoogle Scholar
  • 41 Neumann H P, Bausch B, McWhinney S R, Bender B U, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith W M, Munk R, Manz T, Glaesker S, Apel T W, Treier M, Reineke M, Walz M K, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C ;. Germ-line mutations in nonsyndromic pheochromocytoma.  N Engl J Med. 2002;  346 1459-1466
    CrossrefPubMedGoogle Scholar
  • 42 Gimenez-Roqueplo A P, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin P F, Jeunemaitre X. COMETE Network. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.  Cancer Res. 2003;  63 5615-5621
    PubMedGoogle Scholar
  • 43 Amar L, Strompf L, Plouin P F, Jeunemaitre X, Gimenez-Roqueplo A P. The SDHB and VHL genes should be systematically tested in patients with nonsyndromic pheochromocytoma.  J Hypertens. 2004;  22 (suppl 2) S210
    PubMedGoogle Scholar
  • 44 Lee S C, Chionh S B, Chong S M, Taschner P E. Hereditary paraganglioma due to the SDHD MII mutation in a second Chinese family: a founder effect?.  Laryngoscope. 2003;  113 1055-1058
    PubMedGoogle Scholar
  • 45 Bausch B, Munk R, Schipper J, Hoegerle S, Berger D, Bohm N, Neumann H. SDHD mutations in carotid body tumors and pheochromocytomas: paraganglioma syndrome type 1.  Curr Opin Endocrinol Diabetes. 2003;  10 197-204
    CrossrefPubMedGoogle Scholar
  • 46 Gimm O, Armanios M, Dziema H, Neumann H P, Eng C. Somatic and occult germline mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.  Cancer Research. 2000;  60 6822-6825
    PubMedGoogle Scholar
  • 47 Cascon A, Ruiz-Llorente S, Cebrian A, Telleria D, Rivero J C, Diez J J, Lopez-Ibarra P J, Jaunsolo M A, Benitez J, Robledo M. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.  Eur J Hum Genet. 2002;  10 457-461
    PubMedGoogle Scholar
  • 48 Astuti D, Douglas F, Lennard T W, Aligianis I A, Woodward E R, Evans D G, Eng C, Latif F, Maher E R. Germline SDHD mutation in familial phaechromocytoma.  Lancet. 2001;  357 1181-1182
    CrossrefPubMedGoogle Scholar
  • 49 Benn D E, Croxson M S, Tucker K, Bambach C P, Richardson A L, Delbridge L, Pullan P T, Hammond J, Marsch D J, Robinson B G. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.  Oncogene. 2003;  22 1358-1364
    CrossrefPubMedGoogle Scholar
  • 50 Astuti D, Hart-Holden N, Latif F, Lalloo F, Black G C, Lim C, Moran A, Grossman A B, Hodgson S V, Freemont A, Ramsden R, Eng C, Evans D G, Maher E R. Genetic analysis of mitochondrial complex II subunits SDHD, SDHBand SDHC in paraganglioma and phaeochromocytoma susceptibility.  Clin Endocrinol. 2003;  59 728-733
    CrossrefPubMedGoogle Scholar
  • 51 Maier-Woelfle M, Brandle M, Komminoth P, Saremaslani P, Schmid S, Locher T, Heitz P U, Krull I, Galeazzi R L, Schmid C, Perren A. A novel succinate dehydrogenase subunit B gene mutation, H132P, causes familial malignant sympathetic extraadrenal paragangliomas.  J Clin Endocrinol Metab. 2004;  89 362-367
    CrossrefPubMedGoogle Scholar
  • 52 Young A L, Baysal B E, Deb A, Young W F Jr. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.  J Clin Endocrinol Metab. 2002;  87 4101-4105
    CrossrefPubMedGoogle Scholar
  • 53 Pacak K, Ilias I l. Current approaches to the biochemical diagnosis, localization, and treatment of pheochromocytoma in patients with multiple endocrine neoplasia type 2.  Journal Internal Med. 2005;  in press
    PubMedGoogle Scholar

Pr. J. Bertherat

Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, Pavillon Cornil ·

27, rue du Faubourg Saint-Jacques · 75014, Paris · France

Phone: +33 (1) 58 41 18 95

Fax: +33 (1) 46 33 80 60 ·

Email: jerome.bertherat@cch.ap-hop-paris.fr

      >