MOLECULAR BASIS OF INHERITED CANCER SYNDROMES

在一些Li-Fraumeni综合征(LFS)患者中遗传的P53突变是许多不同来源的肿瘤发生过程中的关键事件。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。这一基因座的图谱应该能够洞察导致不同肿瘤发生的其他遗传事件。此外，由于82%遗传P53突变的LFS患者继承了P53错义突变，我们建立了一个包含内源性P53基因172位氨基酸的Arg to His替换的小鼠模型。这种突变对应于6%的人类肿瘤中175位氨基酸改变的热点突变。在小鼠中比较p53错义和零等位基因将对p53突变体之间的体内差异产生有价值的见解。使用另一种小鼠模型(CE/J)的实验表明，可能改变p53功能的其他遗传事件是通过使用另一种小鼠模型(CE/J)而提出的，在该模型中，p53基因的杂合性或纯合性会导致胚胎死亡。P53的修饰物MOP-1也将在本研究中被映射。

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.