Cancer genomes contain large numbers of somatic mutations but few of these mutations drive tumor development. Current approaches either identify driver genes on the basis of mutational recurrence or approximate the functional consequences of nonsynonymous mutations by using bioinformatic scores. Passenger mutations are enriched in characteristic nucleotide contexts, whereas driver mutations occur in functional positions, which are not necessarily surrounded by a particular nucleotide context. We observed that mutations in contexts that deviate from the characteristic contexts around passenger mutations provide a signal in favor of driver genes. We therefore developed a method that combines this feature with the signals traditionally used for driver-gene identification. We applied our method to whole-exome sequencing data from 11,873 tumor-normal pairs and identified 460 driver genes that clustered into 21 cancer-related pathways. Our study provides a resource of driver genes across 28 tumor types with additional driver genes identified according to mutations in unusual nucleotide contexts.

中文翻译：

---

基于核苷酸背景鉴定癌症驱动基因。

癌症基因组包含大量的体细胞突变，但是这些突变很少驱动肿瘤的发展。当前的方法或者基于突变复发来识别驱动基因，或者通过使用生物信息学评分来近似非同义突变的功能后果。客运突变在特征核苷酸背景下富集，而驱动子突变发生在功能位点，而功能位点不一定被特定核苷酸背景包围。我们观察到，与围绕乘客突变的特征性上下文不同的上下文中的突变提供了有利于驱动基因的信号。因此，我们开发了一种将此功能与传统上用于驱动基因识别的信号相结合的方法。我们将我们的方法应用于来自11的全外显子组测序数据 873对正常肿瘤，并鉴定了460个驱动基因，这些基因聚集成21种与癌症相关的途径。我们的研究提供了横跨28种肿瘤类型的驱动基因资源，以及根据异常核苷酸情况下的突变鉴定出的其他驱动基因。