Whole-genome sequencing can be used to estimate subclonal populations in tumours and this intra-tumoural heterogeneity is linked to clinical outcomes. Many algorithms have been developed for subclonal reconstruction, but their variabilities and consistencies are largely unknown. We evaluated sixteen pipelines for reconstructing the evolutionary histories of 293 localized prostate cancers from single samples, and eighteen pipelines for the reconstruction of 10 tumours with multi-region sampling. We show that predictions of subclonal architecture and timing of somatic mutations vary extensively across pipelines. Pipelines show consistent types of biases, with those incorporating SomaticSniper and Battenberg preferentially predicting homogenous cancer cell populations and those using MuTect tending to predict multiple populations of cancer cells. Subclonal reconstructions using multi-region sampling confirm that single-sample reconstructions systematically underestimate intra-tumoural heterogeneity, predicting on average fewer than half of the cancer cell populations identified by multi-region sequencing. Overall, these biases suggest caution in interpreting specific architectures and subclonal variants.

中文翻译：

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量化突变检测对肿瘤亚克隆重建的影响

全基因组测序可用于估计肿瘤中的亚克隆种群，并且这种肿瘤内异质性与临床结果相关。已经开发了许多用于亚克隆重建的算法，但是它们的变异性和一致性在很大程度上是未知的。我们评估了从单一样本重建293个局部前列腺癌的进化历史的16条管道，以及通过多区域采样重建10个肿瘤的18条管道。我们表明，亚克隆体系结构和体细胞突变时间的预测跨管道有很大不同。管线显示出一致的偏倚类型，其中结合了SomaticSniper和Battenberg的那些偏向于预测癌细胞的均一性，而使用MuTect的那些偏向于预测癌细胞的多度。使用多区域采样的亚克隆重建证实了单样本重建系统地低估了肿瘤内异质性，平均预测不到通过多区域测序鉴定的癌细胞群体的一半。总体而言，这些偏见建议在解释特定架构和亚克隆变体时要谨慎。