An Inherited P53 Point Mutation in a Cancer Prone Family with Li-Fraumeni Syndrome

Abstract

Somatic cells derived from members of a cancer-prone family representing three generations were used to assess mutations in selected regions of p53. Fibroblast DNAs from four family members--the proband, his brother, their father and a paternal aunt, yielded an identical point mutation in codon 245 in only one allele of the p53 gene. This mutation, involving G to A transition (GGC -> GAC) leads to substitution of aspartic acid for glycine at that codon in p53 protein and is not present in NSF DNAs of the proband’s mother or his paternal grandfather, neither of whom are in the cancer-prone lineage. Despite the observed mutation, the level of p53 protein detected in these fibroblasts is comparable to low levels observed in normal control fibroblasts. This is in contrast to the high levels of mutant p53 usually found in tumor cell lines. Thus the mutant p53 in these fibroblasts appears to behave differently as compared to the mutant p53 previously detected in transformed cells. Given the inherited nature of this p53 mutation, the demonstrated role of p53 in tumorigenesis and the location of mutation in a region of the gene known to be critical for its function, it appears that we have identified a primary genetic alteration in this Li-Fraumeni family, a defect which may predispose them to increased susceptibility to cancer.KeywordsPolycythemia VeraBilateral Breast CancerPaternal GrandfatherNormal Skin FibroblastPaternal AuntThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.