EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations:: one-third of doublets occur at five pairs of amino acids
EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations:: one-third of doublets occur at five pairs of amino acids
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DOI：
10.1038/onc.2008.71
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发表时间：
2008-07-17
期刊：
影响因子：
8
通讯作者：
Sommer, S. S.
中科院分区：
文献类型：
--
作者：
Chen, Z.;Feng, J.;Sommer, S. S.
癌症中的双重突变尚未得到很好的研究。我们发现肺癌中表皮生长因子受体（EGFR）酪氨酸激酶（TK）结构域中存在高频率的等位基因体细胞双联体突变。当添加来自文献的二重峰时，共有96个二重峰可用于分析。双联体的总体频率为6%，比在小鼠正常组织中观察到的频率高7倍。所有特征性的双联体都是等位基因的，并且沉默突变很少发生。大约一半的双联体在5个氨基酸处含有12个不同的错义突变中的一个或两个：E709、G719、S768、T790和L 861。在这五个氨基酸的突变很少报告为单态。此外，当包括共同的L 858靶标时，超过三分之一的EGFR双联体是五种特异性错义对之一：G719/E709、G719/S768、G719/L 861、L 858/E709和L 858/T790。结构提示功能：数据表明大多数EGFR双联体与“驱动和乘客”突变机制不一致。EGFR双联体相对于单联体高度偏斜，这与两个单独次优突变的功能选择一致，这两个单独次优突变组合起来具有增强的致癌潜力。
Doublet mutations in cancer are not well studied. We find that allelic somatic doublet mutations are present at high frequency in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain in lung cancers. When doublets from the literature are added, a total of 96 doublets are available for analysis. The frequency of doublets overall is 6%, which is sevenfold greater than that observed in normal tissue in mouse. All characterized doublets are allelic, and silent mutations occur rarely. About half of all doublets contain one or two of 12 distinct missense mutations at five amino acids: E709, G719, S768, T790 and L861. The mutations at these five amino acids are seldom reported as singlets. Moreover, when the common L858 target is included, more than one-third of EGFR doublets are one of five specific missense pairs: G719/E709, G719/S768, G719/L861, L858/E709 and L858/T790. Structure suggests function: The data imply that most EGFR doublets are NOT consistent with a 'driver and passenger' mutation mechanism. EGFR doublets are highly skewed relative to singlets, consistent with functional selection of two individually suboptimal mutations that, in combination, have enhanced oncogenic potential.