Download PDF
Horm Metab Res 2007; 39(6): 461-466
DOI: 10.1055/s-2007-981476
Review

© Georg Thieme Verlag KG Stuttgart · New York

The Molecular Pathogenesis of Childhood Adrenocortical Tumors

M. Q. Almeida 1 , A. C. Latronico 1
  • 1Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
Further Information

Publication History

received 1.11.2006

accepted 18.4.2007

Publication Date:
18 June 2007 (online)

Also available at
    Permissions and Reprints

Abstract

Adrenocortical tumors in children and adolescents are rare events. However, the high incidence of adrenocortical tumors in children from the Southern region of Brazil is particularly remarkable, since it has been estimated to be approximately 10-15 times greater than the worldwide incidence. To date, there are no histological or molecular markers that can reliably distinguish benign from malignant adrenocortical tumors. The study of rare genetic syndromes associated with adrenocortical tumors has greatly contributed to the elucidation of sporadic adrenocortical tumorigenesis. Recently, considerable advances toward understanding the molecular mechanisms of adrenocortical tumorigenesis in Brazilian children and adolescents with sporadic adrenocortical tumors have been made. Some of the molecular aspects of sporadic adrenocortical tumors arising in children and adolescents are reviewed here.

Key words

Adrenocortical tumorigenesis - children - p53 - IGF2 - SF-1

References

  • 1 Young Jr JL, Miller RW. Incidence of malignant tumors in U. S. children.  J Pediatr. 1975;  86 254-258
    PubMedGoogle Scholar
  • 2 Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 2027-2031
    CrossrefPubMedGoogle Scholar
  • 3 Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 1317-1324
    CrossrefPubMedGoogle Scholar
  • 4 Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.  Am J Surg Pathol. 1984;  8 163-169
    CrossrefPubMedGoogle Scholar
  • 5 Mendonca BB, Lucon AM, Menezes CA, Saldanha LB, Latronico AC, Zerbini C, Madureira G, Domenice S, Albergaria MA, Camargo MH. Clinical, hormonal and pathological findings in a comparative study of adrenocortical neoplasms in childhood and adulthood.  J Urol. 1995;  154 2004-2009
    PubMedGoogle Scholar
  • 6 Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients.  Am J Surg Pathol. 2003;  27 867-881
    CrossrefPubMedGoogle Scholar
  • 7 Levine AJ. The p53 tumor-suppressor gene.  N Engl J Med. 1992;  326 1350-1352
    PubMedGoogle Scholar
  • 8 Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers.  Science. 1991;  253 49-53
    CrossrefPubMedGoogle Scholar
  • 9 Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene.  N Engl J Med. 1993;  329 1318-1327
    CrossrefPubMedGoogle Scholar
  • 10 Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein.  Science. 1991;  252 1708-1711
    CrossrefPubMedGoogle Scholar
  • 11 Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B. Genetic changes in human adrenocortical carcinomas.  J Natl Cancer Inst. 1989;  81 518-523
    PubMedGoogle Scholar
  • 12 Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies.  J Clin Endocrinol Metab. 1994;  78 790-794
    CrossrefPubMedGoogle Scholar
  • 13 Lin SR, Lee YJ, Tsai JH. Mutations of the p53 gene in human functional adrenal neoplasms.  J Clin Endocrinol Metab. 1994;  78 483-491
    CrossrefPubMedGoogle Scholar
  • 14 Reincke M, Wachenfeld C, Mora P, Thumser A, Jaursch-Hancke C, Abdelhamid S, Chrousos GP, Allolio B. p53 mutations in adrenal tumors: Caucasian patients do not show the exon 4 “hot spot” found in Taiwan.  J Clin Endocrinol Metab. 1996;  81 3636-3638
    CrossrefPubMedGoogle Scholar
  • 15 Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, 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
  • 16 Latronico AC, Pinto EM, Domenice S, Fragoso MC, Martin RM, Zerbini MC, Lucon AM, Mendonca BB. 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
  • 17 Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.  Science. 1990;  250 1233-1238
    CrossrefPubMedGoogle Scholar
  • 18 Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome.  Nature. 1990;  348 747-749
    CrossrefPubMedGoogle Scholar
  • 19 Malkin D, Jolly KW, Barbier N, Look AT, Friend SH, Gebhardt MC, Andersen TI, Borresen AL, Li FP, Garber J. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms.  N Engl J Med. 1992;  326 1309-1315
    PubMedGoogle Scholar
  • 20 Figueiredo BC, Sandrini R, Zambetti GP, Pereira RM, Cheng C, Liu W, Lacerda L, Pianovski MA, Michalkiewicz E, Jenkins J, Rodriguez-Galindo C, Mastellaro MJ, Vianna S, Watanabe F, Sandrini F, Arram SB, Boffetta P, Ribeiro RC. Penetrance of adrenocortical tumors associated with the germline TP53 R337H mutation.  J Med Genet. 2006;  43 91-96
    PubMedGoogle Scholar
  • 21 Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G, Evans DG, Harris M, Kelsey AM, Birch JM. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.  Am J Hum Genet. 1999;  65 995-1006
    CrossrefPubMedGoogle Scholar
  • 22 Pinto EM, Billerbeck AE, Villares MC, Domenice S, Mendonca BB, Latronico AC. Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors.  Arq Bras Endocrinol Metabol. 2004;  48 647-650
    PubMedGoogle Scholar
  • 23 Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, Nichols PW, Skinner DG, Jones PA, Cote RJ. Accumulation of nuclear p53 and tumor progression in bladder cancer.  N Engl J Med. 1994;  331 1259-1264
    CrossrefPubMedGoogle Scholar
  • 24 Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K, Saito H, Hotta T. Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.  N Engl J Med. 1997;  337 529-534
    CrossrefPubMedGoogle Scholar
  • 25 Pinto EM, Billerbeck AE, Fragoso MC, Mendonca BB, Latronico AC. Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein.  J Clin Endocrinol Metab. 2005;  90 2976-2981
    CrossrefPubMedGoogle Scholar
  • 26 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
    PubMedGoogle Scholar
  • 27 DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.  Nat Struct Biol. 2002;  9 12-16
    CrossrefPubMedGoogle Scholar
  • 28 Achatz MI, Olivier M, Calvez FL, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Rocha JC, Vettore AL, Hainaut P. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families.  Cancer Lett. 2007;  245 96-102
    CrossrefPubMedGoogle Scholar
  • 29 Achatz MI, Olivier M, Calvez FL, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Vargas FR, Casali da Rocha JC, Vettore AL, Hainaut P. Response to “Germline TP53 mutation R337H is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome”, by Ribeiro RC et al.  Cancer Lett. 2007;  247 356-358
    CrossrefPubMedGoogle Scholar
  • 30 Barzilay JI, Pazianos AG. Adrenocortical carcinoma.  Urol Clin North Am. 1989;  16 457-468
    PubMedGoogle Scholar
  • 31 Latronico AC, Reincke M, Mendonca BB, Arai K, Mora P, Allolio B, Wajchenberg BL, Chrousos GP, Tsigos C. No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms.  J Clin Endocrinol Metab. 1995;  80 875-877
    CrossrefPubMedGoogle Scholar
  • 32 Light K, Jenkins PJ, Weber A, Perrett C, Grossman A, Pistorello M, Asa SL, Clayton RN, Clark AJ. Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia?.  Life Sci. 1995;  56 1523-1527
    CrossrefPubMedGoogle Scholar
  • 33 Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos GP, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis.  J Clin Endocrinol Metab. 1997;  82 3054-3058
    CrossrefPubMedGoogle Scholar
  • 34 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 1688-1695
    Google Scholar
  • 35 Reincke M, Karl M, Travis W, Chrousos GP. No evidence for oncogenic mutations in guanine nucleotide-binding proteins of human adrenocortical neoplasms.  J Clin Endocrinol Metab. 1993;  77 1419-1422
    CrossrefPubMedGoogle Scholar
  • 36 Gicquel C, Dib A, Bertagna X, Amselem S, Le Bouc Y. Oncogenic mutations of alpha-Gi2 protein are not determinant for human adrenocortical tumorigenesis.  Eur J Endocrinol. 1995;  133 166-172
    PubMedGoogle Scholar
  • 37 Latronico AC, Mendonca BB, Bianco AC, Villares SM, Lucon MA, Nicolau W, Wajchenberg BL. Calcium-dependent protein kinase-C activity in human adrenocortical neoplasms, hyperplastic adrenals, and normal adrenocortical tissue.  J Clin Endocrinol Metab. 1994;  79 736-739
    CrossrefPubMedGoogle Scholar
  • 38 Yashiro T, Hara H, Fulton NC, Obara T, Kaplan EL. Point mutations of ras genes in human adrenal cortical tumors: absence in adrenocortical hyperplasia.  World J Surg. 1994;  18 455-460
    CrossrefPubMedGoogle Scholar
  • 39 Moul JW, Bishoff JT, Theune SM, Chang EH. Absent ras gene mutations in human adrenal cortical neoplasms and pheochromocytomas.  J Urol. 1993;  149 1389-1394
    PubMedGoogle Scholar
  • 40 Ilvesmaki V, Blum WF, Voutilainen R. Insulin-like growth factor binding proteins in the human adrenal gland.  Mol Cell Endocrinol. 1993;  97 71-79
    CrossrefPubMedGoogle Scholar
  • 41 Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex.  Endocr Rev. 1997;  18 378-403
    CrossrefPubMedGoogle Scholar
  • 42 Weber MM, Fottner C, Schmidt P, Brodowski KM, Gittner K, Lahm H, Engelhardt D, Wolf E. Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis.  Endocrinology. 1999;  140 1537-1543
    CrossrefPubMedGoogle Scholar
  • 43 DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene.  Cell. 1991;  64 849-859
    CrossrefPubMedGoogle Scholar
  • 44 Hao Y, Crenshaw T, Moulton T, Newcomb E, Tycko B. Tumor-suppressor activity of H19 RNA.  Nature. 1993;  365 764-767
    PubMedGoogle Scholar
  • 45 Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene.  Genes Dev. 1995;  9 650-662
    PubMedGoogle Scholar
  • 46 Brannan CI, Dees EC, Ingram RS, Tilghman SM. The product of the H19 gene may function as an RNA.  Mol Cell Biol. 1990;  10 28-36
    PubMedGoogle Scholar
  • 47 Ferguson-Smith AC, Sasaki H, Cattanach BM, Surani MA. Parental-origin-specific epigenetic modification of the mouse H19 gene.  Nature. 1993;  362 751-755
    PubMedGoogle Scholar
  • 48 Hatada I, Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse.  Nat Genet. 1995;  11 204-206
    PubMedGoogle Scholar
  • 49 Ping AJ, Reeve AE, Law DJ, Young MR, Boehnke M, Feinberg AP. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.  Am J Hum Genet. 1989;  44 720-723
    PubMedGoogle Scholar
  • 50 Henry I, Jeanpierre M, Couillin P, Barichard F, Serre JL, Journel H, Lamouroux A, Turleau C, de Grouchy J, Junien C. Molecular definition of the 11p15.5 region involved in Beckwith-Wiedemann syndrome and probably in predisposition to adrenocortical carcinoma.  Hum Genet. 1989;  81 273-277
    PubMedGoogle Scholar
  • 51 Gicquel C, Bertagna X, Schneid H, Francillard-Leblond M, Luton JP, Girard F, Le Bouc Y. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 1994;  78 1444-1453
    CrossrefPubMedGoogle Scholar
  • 52 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;  82 2559-2565
    CrossrefPubMedGoogle Scholar
  • 53 Wilkin F, Gagne N, Paquette J, Oligny LL, Deal C. Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression.  J Clin Endocrinol Metab. 2000;  85 2048-2056
    CrossrefPubMedGoogle Scholar
  • 54 Almeida MQ, Nishi MY, Costa MHS, Fragoso MCBV, Mendonca BB, Latronico AC. Expression profiles of IGF2 and IGF receptor type 1 in childhood adrenocortical tumors: prognostic and therapeutic implications.  J Pediatr Endocrinol Metab. 2006;  19 ((Suppl 3)) 1066-1066
    PubMedGoogle Scholar
  • 55 Logie A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C. Autocrine role of IGF2 in proliferation of human adrenocortical carcinoma NCI H295R cell line.  J Mol Endocrinol. 1999;  23 23-32
    CrossrefPubMedGoogle Scholar
  • 56 Wang Y, Sun Y. Insulin-like growth factor receptor-1 as an anti-cancer target. Blocking transformation and inducing apoptosis.  Curr Cancer Drug Targets. 2002;  2 191-207
    CrossrefPubMedGoogle Scholar
  • 57 Figueiredo BC, Stratakis CA, Sandrini R, DeLacerda L, Pianovsky MA, Giatzakis C, Young HM, Haddad BR. Comparative genomic hybridization analysis of adrenocortical tumors of childhood.  J Clin Endocrinol Metab. 1999;  84 1116-1121
    CrossrefPubMedGoogle Scholar
  • 58 James LA, Kelsey AM, Birch JM, Varley JM. Highly consistent genetic alterations in childhood adrenocortical tumors detected by comparative genomic hybridization.  Br J Cancer. 1999;  81 300-304
    CrossrefPubMedGoogle Scholar
  • 59 Kjellman M, Kallioniemi OP, Karhu R, Hoog A, Farnebo LO, Auer G, Larsson C, Backdahl M. Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy.  Cancer Res. 1996;  56 4219-4223
    PubMedGoogle Scholar
  • 60 Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P. Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications.  Genes Chromosomes Cancer. 2000;  28 145-152
    CrossrefPubMedGoogle Scholar
  • 61 West AN, Neale GA, Pounds S, Figueredo BC, Galindo CR, Pianovski MAD, Oliveira Filho AG, Malkin D, Lalli E, Ribeiro R, Zambetti GP. Gene Expression profiling of childhood adrenocortical tumors.  Cancer Res. 2007;  67 600-608
    CrossrefPubMedGoogle Scholar
  • 62 Keegan CE, Hammer GD. Recent insights into organogenesis of the adrenal cortex.  Trends Endocrinol Metab. 2002;  13 200-208
    CrossrefPubMedGoogle Scholar
  • 63 Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, Parker KL. Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression.  Mol Endocrinol. 1993;  7 852-860
    CrossrefPubMedGoogle Scholar
  • 64 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function.  Endocr Rev. 1997;  18 361-377
    CrossrefPubMedGoogle Scholar
  • 65 Beuschlein F, Mutch C, Bavers DL, Ulrich-Lai YM, Engeland WC, Keegan C, Hammer GD. Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy.  Endocrinology. 2002;  143 3122-3135
    CrossrefPubMedGoogle Scholar
  • 66 Figueiredo BC, Cavalli LR, Pianovski MA, Lalli E, Sandrini R, Ribeiro RC, Zambetti G, DeLacerda L, Rodrigues GA, Haddad BR. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors.  J Clin Endocrinol Metab. 2005;  90 615-619
    CrossrefPubMedGoogle Scholar
  • 67 Pianovski MA, Cavalli LR, Figueiredo BC, Santos SC, Doghman M, Ribeiro RC, Oliveira AG, Michalkiewicz E, Rodrigues GA, Zambetti G, Haddad BR, Lalli E. SF-1 overexpression in childhood adrenocortical tumors.  Eur J Cancer. 2006;  42 1040-1043
    CrossrefPubMedGoogle Scholar
  • 68 Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, Schwarz HP, Kaplan JC, Camerino G, Meitinger T, Monaco AP. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.  Nature. 1994;  372 672-676
    CrossrefPubMedGoogle Scholar
  • 69 Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.  Nature. 1997;  390 311-315
    CrossrefPubMedGoogle Scholar

Correspondence

A. C. LatronicoMD 

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Av. Dr. Enéas de Carvalho Aguiar

155, 2° andar Bloco 6

05403-900, São Paulo

Brasil

Phone: +55/11/30 69 75 12

Fax: +55/11/30 69 75 19

Email: anacl@usp.br

Email: madsonalmeida@gmail.com

      >