Identification of cancer driver genes based on nucleotide context
Identification of cancer driver genes based on nucleotide context
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DOI：
10.1038/s41588-019-0572-y
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发表时间：
2020-02-03
期刊：
影响因子：
30.8
通讯作者：
Sunyaev, Shamil R.
中科院分区：
文献类型：
--
作者：
Dietlein, Felix;Weghorn, Donate;Sunyaev, Shamil R.
MutPanning是一种检测癌症驱动基因的新方法，它可以识别在不寻常的核苷酸背景下具有过量突变的基因。将其应用于11,873对肿瘤正常基因的全外显子组测序数据，确定了460个驱动基因。癌症基因组包含大量体细胞突变，但这些突变很少驱动肿瘤的发展。目前的方法要么在突变复发的基础上识别驱动基因，要么通过使用生物信息学评分来近似非同义突变的功能后果。乘客突变在特征核苷酸环境中丰富，而驱动突变发生在功能位置，这些位置不一定被特定的核苷酸环境所包围。我们观察到，与乘客突变周围的特征环境偏离的环境中的突变提供了一个有利于驱动基因的信号。因此，我们开发了一种方法，将这一特征与传统上用于驱动基因识别的信号相结合。我们将该方法应用于来自11,873对肿瘤正常组的全外显子组测序数据，并确定了460个驱动基因，这些基因聚集在21个癌症相关通路中。我们的研究提供了28种肿瘤类型的驱动基因资源，并根据异常核苷酸背景的突变确定了额外的驱动基因。
MutPanning is a new method to detect cancer driver genes that identifies genes with an excess of mutations in unusual nucleotide contexts. Applying this to whole-exome sequencing data from 11,873 tumor-normal pairs identifies 460 driver genes.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.