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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)

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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.

Key words

p53 mutation - DNA sequencing - Adrenocortical tumor - Inheritance

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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 3 Latronico A C, Chrousos G P. Extensive personal experience: adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 1317-1324
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 9 Malkin D, Li F P. Genetic defect identified in rare cancer syndrome.  Science. 1990;  250 1232-1233
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 13 Levine A J, Momand J, Finlay C A. The p53 tumour suppressor gene.  Nature. 1991;  351 453-456
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 15 Grasso L, Mercer W E. Pathways of p53-dependent apoptosis.  Vitam Horm. 1997;  53 139-173
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 17 Young J L , Miller R W. Incidence of malignant tumors in US children.  J Pediatr. 1975;  86 254-258
    PubMedSearch in Google Scholar
  • 18 Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adrenocortical carcinoma.  Ann Oncol. 1997;  8 423-427
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 20 Sandrini R, Ribeiro R C, DeLacerda L. Childhood adrenocortical tumors.  J Clin Endocrinol Metab. 1997;  82 2027-2031
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 22 Stiller C A, Parkin D M. Geographic and ethnic variations in the incidence of childhood cancer.  Brit Med Bull. 1996;  52 682-703
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 26 Harris C C, Hollstein M. Clinical implications of the p53 tumor-suppressor gene.  N Engl J Med. 1993;  329 1318-1327
    CrossrefPubMedSearch in Google Scholar
  • 27 Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation.  Ann NY Acad Sci. 2000;  910 121-137
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 33 Vogelstein B, Kinzler K W. p53 function and dysfunction.  Cell. 1992;  70 523-526
    CrossrefPubMedSearch in Google Scholar
  • 34 Hussain S P, Harris C C. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens.  Mutat Res. 2000;  462 311-322
    PubMedSearch in Google Scholar
  • 35 Pfeifer G P. p53 mutational spectra and the role of methylated CpG sequences.  Mutat Res. 2000;  450 155-166
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 37 Weiss L M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.  Am J Surg Pathol. 1984;  8 163-169
    CrossrefPubMedSearch in Google Scholar
  • 38 Kjellman M, Larsson C, Backdahl M. Genetic background of adrenocortical tumor development.  World J Surg. 2001;  25 948-956
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar

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