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Published Online First: 20 July 2005. doi:10.1136/jmg.2004.030551
Journal of Medical Genetics 2006;43:91-96
Copyright © 2006 by the BMJ Publishing Group Ltd.

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LETTER TO JMG

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

B C Figueiredo1, R Sandrini2, G P Zambetti5, R M Pereira2, C Cheng7, W Liu7, L Lacerda2, M A Pianovski3, E Michalkiewicz8, J Jenkins6, C Rodriguez-Galindo4, M J Mastellaro9, S Vianna10, F Watanabe11, F Sandrini2, S B I Arram1, P Boffetta12, R C Ribeiro4

1 Centre for Molecular Genetics and Childhood Cancer Research (CEGEMPAC), Clinics Hospital, Federal University of Paraná, Curitiba, PR, Brazil
2 Paediatric Division of Endocrinology, Clinics Hospital, Federal University of Paraná
3 Haematology and Oncology, Clinics Hospital, Federal University of Paraná
4 Department of Hematology-Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
5 Departments of Biochemistry, St Jude Children’s Research Hospital
6 Department of Pathology, St Jude Children’s Research Hospital
7 Department of Biostatistics, St. Jude Children’s Research Hospital
8 Division of Oncological Paediatric Surgery, Erasto Gaertner Hospital, Liga Paranaense de Combate ao Câncer, Curitiba, PR, Brazil
9 Centro Infantil Boldrini, Campinas, SP, Brazil
10 Department of Haematology and Oncology, Hospital dos Servidores de São Paulo, SP, Brazil
11 Division of Haematology and Oncology, Hospital Pequeno Principe, Curitiba, PR, Brazil
12 Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France

Correspondence to:
Dr Raul C Ribeiro
International Outreach Program, Department of Hematology-Oncology, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794, USA; raul.ribeiro{at}stjude.org] Background: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined.

Objective: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation.

Methods: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines.

Results: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%).

Conclusions: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.


Abbreviations: ACT, adrenocortical tumour; LF, Li-Fraumeni syndrome; MLE, maximum likelihood estimator; PBL, peripheral blood lymphocytes

Keywords: TP53; penetrance; adrenocortical tumour; Li-Fraumeni syndrome; childhood adrenocortical carcinoma




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