RESUMEN
The Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome, characterized by a wide spectrum of neoplasms, occurring in children and young adults. The identification of germline TP53 mutations in LFS has given rise to a number of in vitro studies using cultures of cancer cells and non-tumoral fibroblasts presenting germline TP53 mutations. In the present study, we performed a detailed documentation of the pedigree of an LFS family with a comprehensive analysis of genotype-phenotype correlations. We sequenced the TP53 gene and verified that the proband carries a germline nonsense mutation in codon 146 in one allele, the TP53Arg72Pro polymorphism in the second, and other intronic polymorphisms in the TP53 gene. In order to investigate the disruption of the p53 function in a patient presenting this mutation and the TP53Arg72Pro polymorphism who had so far suffered five malignant tumors and a benign meningioma, we tested her fibroblasts in response to DNA damage by evaluating the proliferation rate, apoptosis, and disruption of the TP53 pathway. The proband's heterozygous fibroblasts were not as efficient as control fibroblasts or those of her mother, who carried only the TP53Arg72Pro polymorphism, in causing cell arrest and cell death after DNA damage, which was correlated with diminished TP21 protein levels.
Asunto(s)
Codón sin Sentido , Daño del ADN , Fibroblastos/metabolismo , Mutación de Línea Germinal , Síndrome de Li-Fraumeni/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Ciclo Celular , Proliferación Celular , Células Cultivadas , Codón de Terminación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Etopósido/farmacología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Genotipo , Heterocigoto , Humanos , Síndrome de Li-Fraumeni/metabolismo , Síndrome de Li-Fraumeni/patología , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Polimorfismo Genético , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil. Other genetic alterations are also frequently found in these tumors. This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumors, and how they are related to clinical outcome. Tumor DNA of 12 children with ACT (4 adenomas and 8 carcinomas) and from the blood of their parents was analyzed. All patients showed 11p15 loss of heterozygosity (LOH) in the tumor. In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss. Our data show that 11p15 LOH is a widespread finding in childhood ACT not related with malignancy, contrary to adult ACT. Alterations in the expression of other genes in the same region (e.g., CDKN1C) may contribute to ACT tumorigenesis.
Asunto(s)
Adenoma/genética , Neoplasias de la Corteza Suprarrenal/genética , Sustitución de Aminoácidos , Carcinoma/genética , Cromosomas Humanos Par 11/genética , Genes p53/genética , Factor II del Crecimiento Similar a la Insulina/genética , Pérdida de Heterocigocidad , Mutación Missense , Proteínas de Neoplasias/genética , Síndromes Neoplásicos Hereditarios/genética , Mutación Puntual , Adenoma/epidemiología , Adenoma/mortalidad , Adolescente , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/mortalidad , Factores de Edad , Brasil/epidemiología , Carcinoma/epidemiología , Carcinoma/mortalidad , Niño , Preescolar , Cromosomas Humanos Par 11/ultraestructura , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Impresión Genómica , Mutación de Línea Germinal , Humanos , Lactante , Factor II del Crecimiento Similar a la Insulina/biosíntesis , Proteínas de Neoplasias/biosíntesis , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/mortalidad , Resultado del TratamientoRESUMEN
The steroidogenic factor 1 (SF-1) gene encodes a transcription factor playing a pivotal role in the regulation of adrenogenital development. We have recently shown that SF-1 is amplified in childhood adrenocortical tumours (ACT). This study was aimed to assess if an increase in SF-1 gene copy number was associated with increased protein levels and to study the correlation between SF-1 expression and ACT clinical parameters. An increased SF-1 copy number was detected in eight of the 10 ACT cases studied. Conversely, the SF-1 protein was found to be overexpressed in all cases, compared to normal age-matched adrenal glands. No significant correlation was found between SF-1 protein levels and its gene copy number. Furthermore, no significant correlation existed with histological grade or with the clinical manifestation or evolution of disease. This data show that SF-1 overexpression is widespread in childhood ACT and is likely to play a role in its pathogenesis.