Repurposing Germline Exomes of the Cancer Genome Atlas Demands a Cautious Approach and Sample-Specific Variant Filtering
Repurposing Germline Exomes of the Cancer Genome Atlas Demands a Cautious Approach and Sample-Specific Variant Filtering
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DOI：
10.1142/9789814749411_0020
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发表时间：
2016
影响因子：
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通讯作者：
A. Koire;Panagiotis Katsonis;O. Lichtarge
中科院分区：
文献类型：
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作者：
A. Koire;Panagiotis Katsonis;O. Lichtarge
当试图重现来自全外显子组或基因组测序数据的结果时，可以推进精准医学，产生患者队列所需的时间和费用使数据重新利用成为一个有吸引力的选择。重新利用的第一步是为数据设置一些质量基线，以便结论不是虚假的。这是困难的，因为不同中心、不同诊所甚至不同患者的质量可能存在差异。在这里，我们使用核苷酸取代模式和针对有影响的突变的阴性选择来评估TCGA癌症患者的全外显子组种系突变的质量。我们估计了每个外显子组相对于两个金标准种系外显子组的假阳性变体调用的分数，并发现样本，癌症亚型和机构之间SNV调用的质量存在很大的差异。然后，我们展示了变体特征（例如支持等位基因的读段的平均碱基质量）如何用于鉴定样品特异性过滤参数以优化假阳性调用的去除。我们得出的结论是，虽然这些种系在精准医学方面有许多潜在的应用，但用户应该在使用前评估可用外显子组数据的质量，并执行额外的过滤步骤。
When seeking to reproduce results derived from whole-exome or genome sequencing data that could advance precision medicine, the time and expense required to produce a patient cohort make data repurposing an attractive option. The first step in repurposing is setting some quality baseline for the data so that conclusions are not spurious. This is difficult because there can be variations in quality from center to center, clinic to clinic and even patient to patient. Here, we assessed the quality of the whole-exome germline mutations of TCGA cancer patients using patterns of nucleotide substitution and negative selection against impactful mutations. We estimated the fraction of false positive variant calls for each exome with respect to two gold standard germline exomes, and found large variability in the quality of SNV calls between samples, cancer subtypes, and institutions. We then demonstrated how variant features, such as the average base quality for reads supporting an allele, can be used to identify sample-specific filtering parameters to optimize the removal of false positive calls. We concluded that while these germlines have many potential applications to precision medicine, users should assess the quality of the available exome data prior to use and perform additional filtering steps.