Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; Big Data Institute, University of Oxford, Oxford OX3 7LF, UK.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell. 2021 Apr 15;184(8):2239-2254.e39. doi: 10.1016/j.cell.2021.03.009. Epub 2021 Apr 7.
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
肿瘤内异质性（ITH）是一种治疗抵抗的机制，因此是一个重要的临床挑战。然而，跨癌症类型的 ITH 的程度、起源和驱动因素还了解甚少。为了解决这个问题，我们对跨越 38 种癌症类型的 2658 个癌症样本的全基因组序列进行了广泛的 ITH 特征描述。几乎所有有信息的样本（95.1%）都含有明显的亚克隆扩张的证据，亚克隆之间经常存在分支关系。我们观察到大多数癌症类型中亚克隆驱动突变的正选择，并确定了癌症类型特异性的驱动基因突变、融合、结构变异和拷贝数改变的亚克隆模式，以及亚克隆扩张之间突变过程的动态变化。我们的研究结果强调了 ITH 及其驱动因素在肿瘤进化中的重要性，并提供了一个全面注释的来自全基因组测序数据的亚克隆事件的泛癌症资源。
