Determining the origin of synchronous multifocal bladder cancer by exome sequencing.
Determining the origin of synchronous multifocal bladder cancer by exome sequencing.
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DOI：
10.1186/s12885-015-1859-8
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发表时间：
2015-11-09
期刊：
影响因子：
3.8
通讯作者：
Lack NA
中科院分区：
文献类型：
--
作者：
Acar Ö;Özkurt E;Demir G;Saraç H;Alkan C;Esen T;Somel M;Lack NA
同步多灶性肿瘤常见于膀胱尿路上皮癌。这些物理上独立的肿瘤的起源被认为是通过管腔内迁移（克隆）或致癌物引起的多细胞自发转化（场效应）而发生的。目前还不清楚哪种模型是正确的，有几项研究支持这两种假设。这种不确定性的一个潜在原因可能是以前用于量化这些肿瘤之间关系的基因突变数量很少。为了更好地了解这些肿瘤的遗传谱系，我们使用来自三名患者的多个样本，对同步多灶性pTa尿路上皮膀胱癌进行了高深度的外显子组测序。高置信度单核苷酸变体（SNV）的系统发育分析表明，在所有三名患者中，测序的多灶性膀胱癌均起源于克隆起源（自举值100%）。有趣的是，在两名患者中，最常见的肿瘤相关SNV类型是TpC* 二核苷酸的胞嘧啶突变（Fisher精确检验p < 10−41），可能是由APOBEC介导的脱氨基作用引起的。将这些结果应用到我们的克隆模型中，我们发现TpC* 型突变在祖先分支的SNV中发生的频率是最近的私有分支的2-5倍（p < 10−4），这表明TpC* 突变主要发生在肿瘤发展的早期。这些结果表明，同步多灶性膀胱癌经常出现从克隆起源。我们的数据还表明，APOBEC介导的突变发生在肿瘤发展的早期，可能是非肌肉浸润性尿路上皮膀胱癌肿瘤发生的驱动因素。本文的在线版本（doi：10.1186/s12885-015-1859-8）包含补充材料，可供授权用户使用。
Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC* dinucleotides (Fisher’s exact test p < 10−41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC* type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10−4) suggesting that TpC* mutations largely occurred early in the development of the tumour. These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer. The online version of this article (doi:10.1186/s12885-015-1859-8) contains supplementary material, which is available to authorized users.