Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK.
Nat Genet. 2014 Mar;46(3):225-233. doi: 10.1038/ng.2891. Epub 2014 Feb 2.
Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73-75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development.
透明细胞肾细胞癌 (ccRCC) 可表现出肿瘤内异质性 (ITH)。我们应用多区域外显子组测序 (M-seq) 解析了十例 ccRCC 的遗传结构和进化史。超深度测序在所有病例中均发现了 ITH。我们发现，73%-75% 鉴定出的 ccRCC 驱动异常是亚克隆的，这使得驱动突变的流行率估计变得复杂。ITH 随分析的活检数量增加而增加，但在大多数肿瘤中没有证据表明达到饱和。染色体 3p 缺失和 VHL 异常是唯一普遍存在的事件。在肿瘤进展过程中，CpG 位点的 C>T 转换比例增加。M-seq 允许对 ccRCC 进化进行时间解析，并细化肿瘤发生过程中发生的突变特征。
