Structural and functional impact of cancer-related missense somatic mutations.
Structural and functional impact of cancer-related missense somatic mutations.
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DOI：
10.1016/j.jmb.2011.06.046
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发表时间：
2011-10-21
影响因子：
5.6
通讯作者：
Moult J
中科院分区：
文献类型：
--
作者：
Shi Z;Moult J
一些大规模的癌症体细胞基因组测序项目现在正在识别癌症中的基因变化。评估这些突变的影响对于了解它们在肿瘤发生中的作用是至关重要的。我们使用了SNPs3D，这是一种最初为分析非同义生殖系变异而开发的软件套件，用来鉴定对蛋白质结构和功能有很大影响的单碱基突变。使用了两种机器学习方法，一种是识别破坏蛋白质三维结构稳定的突变，另一种是利用序列保守，并检测对体内蛋白质功能的所有类型的影响。将详细的结构信息结合到分析中，可以详细解释特定情况下突变的功能影响。分析了一组乳腺和结直肠肿瘤的数据。在已知的癌症基因中，发现接近100%的突变会影响蛋白质功能，这支持了这些方法适合于识别驱动突变的观点。总体而言，50%到60%的体细胞错义突变被预测会对结构稳定性产生很大影响，或者更普遍地影响相应蛋白质的功能。这个值类似于所有可能的具有高影响的错义突变的比例，并且远远高于人类群体SNPs的相应比例，约为30%。肿瘤抑制基因中的大多数突变会破坏蛋白质结构的稳定，而癌基因的突变则以更不同的方式发挥作用，包括不太活跃的构象状态的不稳定。这组高影响力的突变包含了可能的驱动因素。
A number of large scale cancer somatic genome sequencing projects are now identifying genetic alterations in cancers. Evaluation of the effects of these mutations is essential for understanding their contribution to tumorigenesis. We have used SNPs3D, a software suite originally developed for analyzing non-synonymous germ line variants, to identify single base mutations with a high impact on protein structure and function. Two machine learning methods are used, one identifying mutations that destabilize protein three dimensional structure, and the other utilizing sequence conservation, and detecting all types of effects on in vivo protein function. Incorporation of detailed structure information into the analysis allows detailed interpretation of the functional effects of mutations in specific cases. Data from a set of breast and colorectal tumors were analyzed. In known cancer genes, approaching 100% of mutations are found to impact protein function, supporting the view that these methods are appropriate for identifying driver mutations. Overall, 50% to 60% of all somatic missense mutations are predicted to have a high impact on structural stability or to more generally affect the function of the corresponding proteins. This value is similar to the fraction of all possible missense mutations that have high impact, and much higher than the corresponding one for human population SNPs, at about 30%. The majority of mutations in tumor suppressors destabilize protein structure, while mutations in oncogenes operate in more varied ways, including destabilization of the less active conformational states. The set of high impact mutations encompass the possible drivers.
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影响因子：
3.7
作者：
Cerami E;Demir E;Schultz N;Taylor BS;Sander C
通讯作者：
Sander C
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Bromberg Y;Rost B
通讯作者：
Rost B
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
11.2
作者：
Carter H;Chen S;Isik L;Tyekucheva S;Velculescu VE;Kinzler KW;Vogelstein B;Karchin R
通讯作者：
Karchin R