Heterozygous TP53stop146/R72P fibroblasts from a Li-Fraumeni syndrome patient with impaired response to DNA damage.

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.