Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
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DOI：
10.1158/1541-7786.mcr-10-0496
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Fronza G
中科院分区：
文献类型：
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作者：
Monti P;Perfumo C;Bisio A;Ciribilli Y;Menichini P;Russo D;Umbach DM;Resnick MA;Inga A;Fronza G
种系 TP53 突变会导致癌症倾向综合征，称为 Li-Fraumeni、Li-Fraumeni 样和有或没有家族史的非综合征倾向。为了探索基因型/表型关联，我们之前采用了基于反式激活的所有种系 p53 突变等位基因的功能分类。与部分缺乏（PD）等位基因相比，严重缺乏（SD）等位基因与更严重的癌症倾向综合征和更多的肿瘤相关。由于突变型 p53 可以发挥显性阴性 (DN) 效应，因此我们探讨了 DN 与临床表现之间的关系。我们推断，在与种系 p53 突变相关的家族性癌症病例中，DN 效应可能更强，其中突变等位基因自受孕以来就与野生型等位基因共存。我们使用基于酵母的定量分析检查了 IARC 种系数据库中描述的 104 个具有单氨基酸取代的 p53 突变等位基因的 (i) 反式激活能力和 (ii) 降低野生型等位基因活性（即 DN 效应）的能力。 p53 等位基因的功能分类随后与临床变量相关。我们证实，仅基于反式激活的分类可以识别具有更严重临床特征的家族性癌症病例。基于 DN 效应的分类使我们能够强调类似的关联，但除了与肿瘤组织患病率的相关性外，没有揭示 SD 等位基因的不同临床亚类。我们得出的结论是，在种系 p53 突变携带者中，基于反式激活的 p53 等位基因分类对于基因型/表型相关性似乎比 DN 效应更重要，并且 TP53 基因的单倍体不足是人类癌症倾向的一个重要因素。
Germline TP53 mutations result in cancer proneness syndromes known as Li-Fraumeni, Li-Fraumeni-like, and nonsyndromic predisposition with or without family history. To explore genotype/phenotype associations, we previously adopted a functional classification of all germline p53 mutant alleles based on transactivation. Severe Deficiency (SD) alleles were associated with more severe cancer proneness syndromes, and a larger number of tumours, compared to Partial Deficiency (PD) alleles. Since mutant p53 can exert Dominant-Negative (DN) effects, we addressed the relationship between DN and clinical manifestations. We reasoned that DN effects might be stronger in familial cancer cases associated with germline p53 mutations, where mutant alleles co-exist with the wild type allele since conception. We examined 104 p53 mutant alleles with single amino acid substitutions described in the IARC germline database for (i) transactivation capability and (ii) capacity to reduce the activity of the wild type allele (i.e., DN effect) using a quantitative yeast-based assay. The functional classifications of p53 alleles were then related to clinical variables. We confirmed that a classification based on transactivation alone can identify familial cancer cases with more severe clinical features. Classification based on DN effects allowed us to highlight similar associations but did not reveal distinct clinical subclasses of SD alleles, except for a correlation with tumour tissue prevalence. We conclude that in carriers of germline p53 mutations transactivation-based classification of p53 alleles appears more important for genotype/phenotype correlations than DN effects and that haplo-insufficiency of the TP53 gene is an important factor in cancer proneness in humans.