Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype:: Lessons from recent developments in the IARC TP53 database
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype:: Lessons from recent developments in the IARC TP53 database
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DOI：
10.1002/humu.20495
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发表时间：
2007-06-01
期刊：
影响因子：
3.9
通讯作者：
Olivier, Magali
中科院分区：
文献类型：
--
作者：
Petitjean, Audrey;Mathe, Ewy;Olivier, Magali
肿瘤抑制基因TP53经常在人类癌症中突变。在所有突变中，超过75％是在各种酵母和人类细胞分析中进行了广泛分析的错义取代。国际癌症研究机构（IARC）TP53数据库（www-p53.iarc.fr）编制了TP53中报道的所有遗传变异。在这里，我们介绍了最近的数据库开发，其中包括有关突变蛋白功能特性的新注释，并对数据库进行系统分析，以确定有助于在不同癌症类型中以及对突变“热点”以及对癌症类型中发生突变“热点”的功能特性。肿瘤的表型。该分析表明，反式激活能力的丧失是选择错义突变的关键因素，并且突变频率的差异与沿TP53编码序列的核苷酸取代速率密切相关。一个有趣的新发现是，在具有遗传性错义突变的患者中，肿瘤发作时的年龄与突变的功能严重程度有关，与保留部分反式激活的突变相比，与早期癌症发作的全反式激活活性的突变与较早的癌症发作有关容量。此外，最常见的突变体中有80％显示出在野生型P53上发挥显性阴性效应（DNE）的能力，而研究的频率较低的突变体中只有45％，这表明DNE可能在塑造突变模式中起作用。这些结果为塑造突变模式并影响突变表型的因素提供了新的见解，这些因素可能具有临床意义。
The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.