Foo Jasmine, Liu Lin L, Leder Kevin, Riester Markus, Iwasa Yoh, Lengauer Christoph, Michor Franziska
Department of Mathematics, University of Minnesota Twin Cities, St. Paul, Minnesota, United States of America.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States of America.
PLoS Comput Biol. 2015 Sep 17;11(9):e1004350. doi: 10.1371/journal.pcbi.1004350. eCollection 2015 Sep.
The traditional view of cancer as a genetic disease that can successfully be treated with drugs targeting mutant onco-proteins has motivated whole-genome sequencing efforts in many human cancer types. However, only a subset of mutations found within the genomic landscape of cancer is likely to provide a fitness advantage to the cell. Distinguishing such "driver" mutations from innocuous "passenger" events is critical for prioritizing the validation of candidate mutations in disease-relevant models. We design a novel statistical index, called the Hitchhiking Index, which reflects the probability that any observed candidate gene is a passenger alteration, given the frequency of alterations in a cross-sectional cancer sample set, and apply it to a mutational data set in colorectal cancer. Our methodology is based upon a population dynamics model of mutation accumulation and selection in colorectal tissue prior to cancer initiation as well as during tumorigenesis. This methodology can be used to aid in the prioritization of candidate mutations for functional validation and contributes to the process of drug discovery.
传统观点认为癌症是一种可通过靶向突变癌蛋白的药物成功治疗的基因疾病,这推动了对多种人类癌症类型进行全基因组测序的工作。然而,在癌症基因组格局中发现的突变只有一部分可能为细胞提供适应性优势。区分此类“驱动”突变与无害的“乘客”事件对于在疾病相关模型中优先验证候选突变至关重要。我们设计了一种名为“搭便车指数”的新型统计指标,该指标根据横断面癌症样本集中的改变频率反映任何观察到的候选基因是乘客改变的概率,并将其应用于结直肠癌的突变数据集。我们的方法基于癌症发生前以及肿瘤发生过程中结直肠组织中突变积累和选择的群体动力学模型。这种方法可用于帮助对候选突变进行功能验证的优先级排序,并有助于药物发现过程。