Horm Metab Res 2005; 37(4): 231-235
DOI: 10.1055/s-2005-861373
Original Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Inheritance of R337H p53 Gene Mutation in Children with Sporadic Adrenocortical Tumor

F.  Sandrini1 , D.  P.  Villani3 , S.  Tucci2 , A.  C.  Moreira1 , M.  de Castro1 , L.  L.  K.  Elias3
  • 1 Department of Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, SP, Brazil
  • 2 Department of Surgery and Anatomy, School of Medicine of Ribeirao Preto, University of Sao Paulo, SP, Brazil
  • 3 Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, SP, Brazil
Further Information

Publication History

Received 23 July 2004

Accepted after revision 21 October 2004

Publication Date:
13 June 2005 (online)

Abstract

Adrenocortical tumors (ACTs) are frequent in Brazil. The mechanisms of adrenal tumorigenesis remain poorly established; the R337H germline mutation in the p53 gene has previously been associated with ACTs in Brazilian children. We investigated the frequency and inheritance of R337H p53 mutation as well as genotype and phenotype correlation in 21 children and 5 adult patients with ACTs. DNA was extracted from peripheral blood cells and/or tumor tissue for sequencing exon 10 of the p53 gene. Nine sets of parents of patients with p53 mutation were also submitted to mutational analysis. Virilization was the most common clinical sign in children with or without Cushing’s syndrome. Two members of the adult group showed asymptomatic adrenal incidentalomas, two showed virilization, and one presented with Cushing’s syndrome. Sixteen children with ACTs had peripheral blood available, and twelve of them (75 %) showed the heterozygous R337H p53 gene mutation. The R337H mutation was found in fifteen samples of the nineteen tumor specimens available (78.9 %). Among the nine sets of parents of the patients with R337H mutation, eight showed the same mutation with heterozygosity in one of the parents. None of the parents showed ACTs or any other neoplasia at the time of the study. Only one adult patient with an ACT revealed the same R337H p53 germline mutation. There was no association between the presence of germline or tissue R337H p53 mutation and malignancy at diagnosis. We confirmed the high frequency of R337H p53 mutation in Brazilian children with sporadic ACTs. The R337H p53 mutation was inherited from one of the parents of the patients, and there was no association between the presence of this mutation and tumor malignancy in children. The founder effect of R337H p53 mutation and the role of environmental mutagens contributing to the geographical clustering and high prevalence of ACTs in Brazilian children remain to be established.

References

  • 1 Gicquel C, Leblond-Francillard M, Bertagna X, Louvel A, Chapuis Y, Luton J P, Girard F, Le Bouc Y. Clonal analysis of human adrenocortical carcinomas and secreting adenomas.  Clin Endocrinol. 1994;  40 465-477
  • 2 Beuschlein F, Reincke M, Karl M, Travis W D, Jaursch-Hancke C, Abdelhamid S, Chrousos G P, Allolio B. Clonal composition of human adrenocortical neoplasms.  Cancer Res. 1994;  54 4927-4932
  • 3 Latronico A C, Chrousos G P. Extensive personal experience: adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 1317-1324
  • 4 Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos G P, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis.  J Clin Endocrinol Metab. 1997;  82 3054-3058
  • 5 Bornstein S R, Stratakis C A, Chrousos G P. Adrenocortical tumors: recent advances in basic concepts and clinical management.  Ann Intern Med. 1999;  130 759-771
  • 6 Figueiredo B C, Stratakis C A, Sandrini R, DeLacerda L, Pianovsky M A, Giatzakis C, Young H M, Haddad B R. Comparative genomic hybridization analysis of adrenocortical tumors of childhood.  J Clin Endocrinol Metab. 1999;  84 1116-1121
  • 7 Koch C A, Pacak K, Chrousos G P. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors.  J Clin Endocrinol Metab. 2002;  87 5367-5384
  • 8 Li F P, Fraumeni J F . Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome.  J Natl Cancer Inst. 1969;  43 1365-1373
  • 9 Malkin D, Li F P. Genetic defect identified in rare cancer syndrome.  Science. 1990;  250 1232-1233
  • 10 Malkin D, Li F P, Strong L C, Fraumeni J F , Nelson C E, Kim D H, Kassel J, Gryka M A, Bischoff F Z, Tainsky M A. Friend SH. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.  Science. 1990;  250 1233-1238
  • 11 Srivastava S, Zou Z Q, Pirollo K, Blattner W, Chang E H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome.  Nature. 1990;  348 747-749
  • 12 Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families.  Am J Pathol. 1997;  150 1-13
  • 13 Levine A J, Momand J, Finlay C A. The p53 tumour suppressor gene.  Nature. 1991;  351 453-456
  • 14 Chen X, Ko L J, Jayaraman L, Prives C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells.  Genes Dev. 1996;  10 2438-2451
  • 15 Grasso L, Mercer W E. Pathways of p53-dependent apoptosis.  Vitam Horm. 1997;  53 139-173
  • 16 Ilvesmaki V, Kahri A I, Miettinen P J, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas.  J Clin Endocrinol Metab. 1993;  77 852-858
  • 17 Young J L , Miller R W. Incidence of malignant tumors in US children.  J Pediatr. 1975;  86 254-258
  • 18 Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adrenocortical carcinoma.  Ann Oncol. 1997;  8 423-427
  • 19 Lack E E, Mulvihill J J, Travis W D, Kozakewich H P. Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors.  Pathol Annu. 1992;  27 1-53
  • 20 Sandrini R, Ribeiro R C, DeLacerda L. Childhood adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 2027-2031
  • 21 Mendonca B B, Lucon A M, Menezes C A, Saldanha L B, Latronico A C, Zerbini C, Madureira G, Domenice S, Albergaria M A, Camargo M H, Halpern A, Liberma B, Arnhold I JP, Bloise W, Andriolo A, Nicolau W, Silva F AQ, Wroclaski E, Arap S, Wajchenberg B L. Clinical, hormonal and pathological findings in a comparative study of adrenocortical neoplasms in childhood and adulthood.  J Urol. 1995;  154 2004-2009
  • 22 Stiller C A, Parkin D M. Geographic and ethnic variations in the incidence of childhood cancer.  Brit Med Bull. 1996;  52 682-703
  • 23 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
  • 24 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 Endocrino Metab. 2001;  86 4970-4973
  • 25 Medeiros L J, Weiss L M. New developments in the pathologic diagnosis of adrenal cortical neoplasms. A review.  Am J Clin Pathol. 1992;  97 73-83
  • 26 Harris C C, Hollstein M. Clinical implications of the p53 tumor-suppressor gene.  N Engl J Med. 1993;  329 1318-1327
  • 27 Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation.  Ann NY Acad Sci. 2000;  910 121-137
  • 28 Soussi T, May P. Structural aspects of the p53 protein in relation to gene evolution: a second look.  J Mol Biol. 1996;  260 623-637
  • 29 Reed M, Woelker B, Wang P, Wang Y, Anderson M E, Tegtmeyer P. The C-terminal domain of p53 recognizes DNA damaged by ionizing radiation.  Proc Natl Acad Sci USA. 1995;  92 9455-9459
  • 30 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.  Nature Struct Biol. 2002;  9 12-16
  • 31 Greenblatt M S, Bennett W P, Hollstein M, Harris C C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.  Cancer Res. 1994;  54 4855-4878
  • 32 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
  • 33 Vogelstein B, Kinzler K W. p53 function and dysfunction.  Cell. 1992;  70 523-526
  • 34 Hussain S P, Harris C C. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens.  Mutat Res. 2000;  462 311-322
  • 35 Pfeifer G P. p53 mutational spectra and the role of methylated CpG sequences.  Mutat Res. 2000;  450 155-166
  • 36 Van Wijngaarden E, Stewart P A, Olshan A F, Savitz D A, Bunin G R. Parental occupational exposure to pesticides and childhood brain cancer.  Am J Epidemiol. 2003;  157 989-997
  • 37 Weiss L M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.  Am J Surg Pathol. 1984;  8 163-169
  • 38 Kjellman M, Larsson C, Backdahl M. Genetic background of adrenocortical tumor development.  World J Surg. 2001;  25 948-956
  • 39 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
  • 40 Shields P G, Harris C C. Cancer risk and low-penetrance susceptibility genes in gene-environment interactions.  J Clin Oncol. 2000;  18 2309-2315

Lucila Leico Kagohara Elias

Department of Physiology · School of Medicine of Ribeirao Preto · University of Sao Paulo

Avenida dos Bandeirantes, 3900 - Monte Alegre · CEP: 14049-900 Ribeirao Preto - SP · Brazil ·

Phone: + 55 16 602 3057

Fax: + 55 16 633 0017

Email: llelias@fmrp.usp.br