Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

• Published in: Journal of medical genetics 2006-01, Vol.43 (1), p.91-96
• Main Authors: Figueiredo, B C, Sandrini, R, Zambetti, G P, Pereira, R M, Cheng, C, Liu, W, Lacerda, L, Pianovski, M A, Michalkiewicz, E, Jenkins, J, Rodriguez-Galindo, C, Mastellaro, M J, Vianna, S, Watanabe, F, Sandrini, F, Arram, S B I, Boffetta, P, Ribeiro, R C
• Format: Article
• Language: English
• Subjects: ACT; Adrenal Cortex Neoplasms - genetics; adrenocortical tumour; Age; Age Distribution; Biological and medical sciences; Cancer; Cardiology. Vascular system; Child; Child, Preschool; childhood adrenocortical carcinoma; Deoxyribonucleic acid; DNA; Families & family life; Female; General aspects. Genetic counseling; Genes; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation - genetics; Humans; Infant; Letter to JMG; Li-Fraumeni syndrome; Male; maximum likelihood estimator; Medical genetics; Medical sciences; MLE; Mutation; PBL; Pedigree; Penetrance; peripheral blood lymphocytes; Polymerase chain reaction; Proteins; Risk Factors; TP53; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2004.030551

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.