Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.
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DOI：
10.1038/nbt.2514
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发表时间：
2013-03
影响因子：
46.9
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中科院分区：
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体点替换的检测是确定癌症基因组特征的关键步骤。癌症中的突变很少见(0.1-100/Mb)，通常只发生在测序细胞的一部分中，要么是由于正常细胞的污染，要么是由于肿瘤的异质性。因此，突变调用方法需要既具有特异性，避免假阳性，又对检测克隆性和亚克隆性突变敏感。现有方法对低等位基因突变的敏感性降低，突显了对改进和系统评估突变检测方法的迫切需要。在这里，我们介绍了MuTect，这是一种基于贝叶斯分类器的方法，旨在检测等位基因比例非常低的体细胞突变，只需要几次支持读取，然后是一组精心调整的过滤器，以确保高特异性。我们还描述了新的基准方法，这些方法使用真实的测序数据来评估作为测序深度、碱基质量和等位基因分数的函数的敏感性和特异性。与其他方法相比，MuTect具有更高的敏感性和相似的特异性，特别是对等位基因比例低至0.1及以下的突变，这使得MuTect特别适用于研究标准外显子组和基因组测序数据中的癌症亚克隆及其进化。
Detection of somatic point substitutions is a key step in characterizing the cancer genome. Mutations in cancer are rare (0.1–100/Mb) and often occur only in a subset of the sequenced cells, either due to contamination by normal cells or due to tumor heterogeneity. Consequently, mutation calling methods need to be both specific, avoiding false positives, and sensitive to detect clonal and sub-clonal mutations. The decreased sensitivity of existing methods for low allelic fraction mutations highlights the pressing need for improved and systematically evaluated mutation detection methods. Here we present MuTect, a method based on a Bayesian classifier designed to detect somatic mutations with very low allele-fractions, requiring only a few supporting reads, followed by a set of carefully tuned filters that ensure high specificity. We also describe novel benchmarking approaches, which use real sequencing data to evaluate the sensitivity and specificity as a function of sequencing depth, base quality and allelic fraction. Compared with other methods, MuTect has higher sensitivity with similar specificity, especially for mutations with allelic fractions as low as 0.1 and below, making MuTect particularly useful for studying cancer subclones and their evolution in standard exome and genome sequencing data.
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64.8
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Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
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Wigler M
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Lee, Ryan S.;Stewart, Chip;Roberts, Charles W. M.
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Roberts, Charles W. M.