MOLECULAR BASIS OF INHERITED CANCER SYNDROMES

在一些患有Li-Fraumeni综合征（LFS）的个体中遗传的p53突变在许多不同来源的肿瘤的发展中是一个关键事件。然而，最近的数据表明，其他基因改变也会导致LFS典型的癌症易感性。该基因座的定位将有助于了解导致多种肿瘤发生的其他遗传事件。此外，由于遗传p53突变的LFS患者中有82%遗传了p53的错义突变，我们创建了一个小鼠模型，该模型包含了内源性p53基因172个氨基酸上的一个arg替换。这种突变对应于6%的人类肿瘤中175个氨基酸的热点突变。在小鼠中比较p53错义等位基因和零等位基因将为了解p53突变体在体内的差异提供有价值的见解。在另一种小鼠模型（CE/J）的实验中，p53位点的杂合性或纯合性会导致胚胎致死性，这表明可能改变p53功能能力的其他遗传事件。p53的修饰子mop1也将在本研究中被绘制。

Mutation of p53, inherited in some individuals with Li-Fraumeni Syndrome (LFS), is a critical event in the elaboration of many tumors of diverse origin. Recent data, however, suggest that other genetic alterations also result in the cancer predisposition typical for LFS. The mapping of this locus should yield insight into other genetic events that lead to the genesis of diverse tumor. In addition, since 82% of LFS patients inheriting mutations of p53 inherit a missense mutation in p53, we have created a mouse model containing an arg to his substitution at amino acid 172 of the endogenous p53 gene. This mutation corresponds to the hot spot mutation at amino acid 175 altered in 6% of human tumors. Comparison of p53 missense and null alleles in the mouse will yield valuable insight into the in vivo differences between p53 mutants. Additional genetic events that may modify the ability of p53 to function are suggested by experiments using another mouse model (CE/J) in which heterozygosity or homozygosity at the p53 locus results in embryo lethality. This modifier of p53, mop 1, will also be mappe4d in this study.