Molecular basis of the Li-Fraumeni syndrome:: an update from the French LFS families
Molecular basis of the Li-Fraumeni syndrome:: an update from the French LFS families
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DOI：
10.1136/jmg.2008.057570
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发表时间：
2008-08-01
影响因子：
4
通讯作者：
Frebourg, T.
中科院分区：
文献类型：
--
作者：
Bougeard, G.;Sesboue, R.;Frebourg, T.
我们对474个提示为Li-Fraumeni综合征（LFS）的法国家庭进行了广泛的TP 53分析，其中包括232个符合Chompret标准的家庭。我们在82个家族（17%）中鉴定出TP 53的生殖系改变，其中67/232个家族符合Chompret标准（29%），15/242个家族不符合这些标准（6%）。大多数的改变对应于错义突变（67%），我们在四个家庭中发现了基因组缺失，删除了整个TP 53基因座，启动子和非编码外显子1，或外显子2-10。这些结果代表了一个明确的论点，表明LFS的结果从TP 53单倍缺陷。肿瘤发病的平均年龄之间有显着差异的患者窝藏TP 53错义突变和其他类型的改变，错义突变与9年前的肿瘤发病。这些结果证实，错义突变不仅p53，而且还具有额外的致癌作用。因此，TP 53的生殖系改变导致功能丧失与肿瘤发病的年龄较晚相关，并且在40岁后诊断出肿瘤的非典型LFS家族中应考虑此类突变的存在。
We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.