Molecular Mutagenesis and DNA Repair Unit, Department of Epidemiology and Prevention, National Cancer Research Institute (IST), Largo Rosanna Benzi, 10, Genova 16132, Italy.
Mol Cancer Res. 2011 Mar;9(3):271-9. doi: 10.1158/1541-7786.MCR-10-0496. Epub 2011 Feb 22.
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 TP53 mutant alleles based on transactivation. Severe deficiency (SD) alleles were associated with more severe cancer proneness syndromes, and a larger number of tumors, compared with partial deficiency (PD) alleles. Because 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 TP53 mutations, where mutant alleles coexist 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 tumor tissue prevalence. We conclude that in carriers of germline TP53 mutations transactivation-based classification of TP53 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.
胚系 TP53 突变导致癌症易感性综合征，称为 Li-Fraumeni、Li-Fraumeni 样和非综合征性易感性，伴有或不伴有家族史。为了探讨基因型/表型相关性，我们之前采用了基于反式激活的所有胚系 TP53 突变等位基因的功能分类。严重缺陷（SD）等位基因与更严重的癌症易感性综合征和更多的肿瘤相关，与部分缺陷（PD）等位基因相比。由于突变 p53 可以发挥显性负（DN）效应，我们研究了 DN 与临床表现之间的关系。我们推断，DN 效应在与胚系 TP53 突变相关的家族性癌症病例中可能更强，因为突变等位基因自受孕以来与野生型等位基因共存。我们使用定量酵母测定法检查了 IARC 胚系数据库中描述的 104 个具有单个氨基酸取代的 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的能力（即 DN 效应）。然后将 p53 等位基因的功能分类与临床变量相关联。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 效应的分类允许我们突出类似的关联，但除了与肿瘤组织流行率相关外，并未揭示 SD 等位基因的独特临床亚类。我们得出结论，在携带胚系 TP53 突变的个体中，基于反式激活的 TP53 等位基因分类对于基因型/表型相关性似乎比 DN 效应更为重要，并且 TP53 基因的单倍体不足是人类癌症易感性的重要因素。
