Systematic Functional Annotation of Somatic Mutations in Cancer
Systematic Functional Annotation of Somatic Mutations in Cancer
复制标题
癌症体细胞突变的系统功能注释
DOI：
10.1016/j.ccell.2018.01.021
复制
发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Ng, Patrick Kwok-Shing;Li, Jun;Mills, Gordon B.
绝大多数癌症体细胞突变的功能影响尚不清楚，这是实施精确肿瘤学的关键知识缺口。在这里，我们报道了一个中等吞吐量的功能基因组平台的开发，包括高效的突变产生，使用两个生长因子依赖的细胞模型进行灵敏的活性分析，以及选择异常的信号效应的功能蛋白质组学分析。我们应用该平台来注释>；1000个基因组异常，包括基因放大、点突变、插入和基因融合，潜在地使临床可操作基因的驱动突变数量翻了一番。此外，该平台足够敏感，可以识别实力较弱的司机。我们的数据可通过用户友好的公共数据门户访问。我们的研究将有助于生物标志物的发现、预测算法的改进和药物的开发。
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.