Exp Clin Endocrinol Diabetes 2007; 115(3): 175-178
DOI: 10.1055/s-2007-970411
Review Article

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Insights into the Molecular Biology of Adrenocortical Tumors

L. Groussin 1 , J. Bertherat 1 , C. Gicquel 1 , Y. le Bouc 1 , X. Bertagna 1
  • 1Clinique des Maladies Endocriniennes et Métaboliques, and Endocrinology Department, Institut Cochin Faculté de Médecine René and Laboratoire d'Explorations Fonctionnelles Trousseau, and the COMETE network, Paris, France
Further Information

Publication History

received 15. 8. 2005 first decision 27. 11. 2006

accepted 22. 1. 2007

Publication Date:
11 April 2007 (online)

Introduction

Adrenocortical tumors are rare tumors which can cause morbidity secondary to hypersecretion (i. e. Cushing's syndrome in adrenocortical adenoma or carcinoma, mineralocorticoid excess in Conn's adenoma) or to their oncogenic growth and metastases.

In the recent years progress has been made in our understanding of the pathophysiology of these endocrine tumors ([Latronico and Chrousos, 1997]; [Bornstein et al., 1999]; [Reincke et al., 2000]; [Bertherat et al., 2002]). Some molecular mechanisms of hormone hypersecretion or growth of adrenocortical tumors have been unraveled this last decade and offer new support to our understanding of adrenocortical tumor development. In particular, studies of familial forms of adrenocortical tumors have given us new insight in the genetics of these tumors. Some of these advances have already lead to new therapeutical or diagnostic approaches.

We will not provide here an extensive review of all studies that have been performed in adrenocortical tumors; we will rather focus on some aspects that are thought to be of major interest.

References

  • 1 Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma.  Clin Endocrinol. 2004;  60 273-287
  • 2 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
  • 3 Bertherat J, Gicquel C, Le Bouc Y, Bertagna X. Molecular genetics of adrenal tumours. In: John AH Wass and Stephen M Shalet, (eds) Oxford textbook of Endocrinology and Diabetes. Oxford: Oxford University Press 2002: 831-842
  • 4 Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA. 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
  • 5 Bertherat J, Contesse V, Louiset E, Barrande G, Duparc C, Groussin L, Emy P, Bertagna X, Kuhn JM, Vaudry H, Lefebvre H. In vivo and in vitro screening for illegitimate receptors in AIMAH causing Cushing's syndrome: identification of two cases of gonadotropin/GIP-dependent hypercortisolism.  J Clin Endocrinol Metab. 2005;  90 1302-1310
  • 6 Beuschlein F, Reincke M, Karl M, Travis WD, Jaursch-Hancke C, Abdelhamid S, Chrousos GP, Allolio B. Clonal composition of human adrenocortical neoplasms.  Cancer Res. 1994;  54 4927-4932
  • 7 Bornstein SR, Stratakis CA, Chrousos GP. Adrenocortical tumors: recent advances in basic concepts and clinical management.  Ann Intern Med. 1999;  130 759-771
  • 8 Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity.  Medicine (Baltimore). 1985;  64 270-283
  • 9 De Fraipont F, El Atifi M, Le Moigne G, Defaye G, Houlgatte R, Bertherat J, Bertagna X, Plouin PF, Baudin E, Berger F, Gicquel C, Chabre O, Feige JJ. Gene expression profiling of human adrenocortical tumors using complementary cDNA micro-arrays identifies several candidate genes as markers of malignancy.  J Clin Endocrinol Metab. 2005;  90 1819-1829
  • 10 Gicquel C, Leblond-Francillard M, Bertagna X, Louvel A, Chapuis Y, Luton JP, Girard F, Le Bouc Y. Clonal analysis of human adrenocortical carcinomas and secreting-adenomas.  Clin Endocrinol (Oxf). 1994;  40 465-477
  • 11 Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, Louvel A, Luton JP, Le Bouc Y. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors. Study on a series of 82 tumors.  J Clin Endocrinol Metab. 1997;  87 2559-2565
  • 12 Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le Bouc Y. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors.  Cancer Res. 2001;  61 6762-6767
  • 13 Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG, Thompson NW, Taylor JM, Hanash SM. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis.  Am J Pathol. 2003;  162 521-531
  • 14 Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, 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
  • 15 Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, Luton JP, 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
  • 16 Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA. 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
  • 17 Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.  Hum Mol Genet. 2000;  9 3037-3046
  • 18 Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Hoog A, Gray S, Farnebo LO, 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
  • 19 Lacroix A, Bolte E, Tremblay J, Dupre J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R. et al . Gastric inhibitory polypeptide-dependent cortisol hypersecretion-a new cause of Cushing's syndrome.  N Engl J Med. 1992;  327 974-980
  • 20 Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome.  Endocrinol Rev. 2001;  22 75-110
  • 21 Latronico AC, Chrousos G. Extensive personal experience: adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  85 1317-1324
  • 22 Logié A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line.  J Mol Endocrinol. 1999;  23 23-32
  • 23 Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, 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 1195-1201
  • 24 Pilon C, Pistorello M, Moscon A, Altavilla G, Pagotto U, Boscaro M, Fallo F. Inactivation of the p16 tumor suppressor gene in adrenocortical tumors.  J Clin Endocrinol Metab. 1999;  84 2776-2779
  • 25 Reincke M, Beuschlein F, Slawik M, Borm K. Molecular adrenocortical tumourigenesis.  Eur J Clin Invest. 2000;  30 63-68
  • 26 Reznik Y, Allali-Zerah V, Chayvialle A, Leroyer R, Leymarie P, Travert G, Lebrethon MC, Budi I, Balliere AM, Mahoudeau J. Food-dependent Cushing's syndrome mediated by aberrant adrenocortical sensitivity to gastric inhibitory polypeptide.  N Engl J Med. 1992;  327 981-986
  • 27 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.  N Engl J Med. 1991;  325 1688-1716

Correspondence

X. Bertagna

Clinique des Maladies

Endocriniennes et Métaboliques

Hôpital Cochin

27 rue du Fg-St-Jacques

75014 Paris

France

Phone: +33/1/58 41 17 90

Fax: +33/1/46 33 80 60

Email: xavier.bertagna@cch.aphp.fr

    >