Identification and characterization of Li-Fraumeni syndrome families: Molecular and in vitro analysis and development of an in vivo model

The Li-Fraumeni Syndrome (LFS) is an inherited predisposition to the development of a diverse spectrum of malignancies that manifest at a much younger age than in the general population. Although rare, studies of the syndrome have led to the elucidation of mechanisms of cancer development and the discovery that the most common genetic abnormality in these families is a germline heterozygous mutation in the p53 tumor suppressor gene. The goal of the studies presented was to improve our understanding of the molecular genotype and to refine the phenotypic definition of LFS with a view to develop an in vivo model that would better represent the human syndrome. The first section of the thesis provides an overview of LFS and its molecular associations while subsequent sections outline the studies relevant to the genotype/phenotype classification of this syndrome.; First, screening and analysis of the germline p53 status of pediatric patients who presented with sporadic component tumors of the syndrome (brain tumors and adrenocortical tumors) clarifies the role that p53 plays in the genesis of these tumors and identifies the risk within the general population of a patient harboring a p53 mutation. Second, through both epidemiologic and functional studies, a common single nucleotide polymorphism at codon 72 of the p53 gene was examined. The results are inconclusive whether this polymorphism has an important role in modifying the cancer phenotype. Next, in vitro studies were completed on an LFS family with a complex heterozygous p53 mutation identified in the proband, illustrating the variable contribution that each mutation confers to loss of wild-type p53 function. Studies of p16INK4a suggest that this candidate gene does not play a significant role in cancer predisposition in LFS families without p53 mutations. Finally, the development of an in vivo mouse model for LFS was initiated. Once completed, these mouse models will offer a novel approach to determine new therapeutic options for the treatment of patients with germline and somatic p53 mutations. These studies, therefore, provide a better global understanding of the genotype and phenotype of LFS and add insight into the role of germline p53 alterations in human carcinogenesis.