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Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

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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