Mutational heterogeneity in cancer and the search for new cancer genes
Mutational heterogeneity in cancer and the search for new cancer genes
复制标题
DOI：
--
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
M. Lawrence;P. Stojanov;P. Polak;G. Kryukov;K. Cibulskis;A. Sivachenko;S. Carter;C. Stewart;
中科院分区：
文献类型：
--
作者：
M. Lawrence;P. Stojanov;P. Polak;G. Kryukov;K. Cibulskis;A. Sivachenko;S. Carter;C. Stewart;
目前主要的国际项目正在进行中，目的是建立一个全面的目录，列出所有与癌症的发生和发展有关的基因。这些研究包括对匹配的肿瘤-正常样本进行测序，然后进行数学分析，以确定那些突变比预期的随机突变更频繁的基因。在这里，我们描述了癌症基因组研究的一个基本问题：随着样本量的增加，当前分析方法产生的假定重要基因列表迅速增加到数百个。这份清单包括许多不可信的基因（比如那些编码嗅觉受体和肌肉蛋白titin的基因），这表明大量的假阳性结果掩盖了真正的驱动因素。在这里，我们表明这个问题主要源于突变异质性，并提供了一种新的分析方法MutSigCV来解决这个问题。我们将MutSigCV应用于3,083对肿瘤-正常对的外显子组序列，发现了癌症类型内的突变频率和谱的异常变化，这揭示了突变过程和疾病病因，以及（ii）整个基因组的突变频率，这与DNA复制时间和转录活性密切相关。通过将突变异质性纳入分析，MutSigCV能够消除大多数明显的人为发现，并允许真正的癌症基因引起人们的注意。， ， ，
Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention. , , ,