Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer
Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer
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DOI：
10.1073/pnas.1313580111
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发表时间：
2014-02-11
影响因子：
11.1
通讯作者：
Trump, Donald L.
中科院分区：
文献类型：
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作者：
Morrison, Carl D.;Liu, Pengyuan;Trump, Donald L.
利用全基因组分析，我们对5例来自肌肉浸润性膀胱移行细胞癌(TCC-UB)患者的膀胱肿瘤进行了测序，并鉴定了一系列基因组异常。在三个肿瘤中，注意到复杂的基因改变。这三个人都有肿瘤蛋白P53突变和相对较多的单核苷酸变异(SNV；平均每兆数据库11.2个)、结构变异(SVS；平均46个)，或两者兼而有之。这一组的最大特点是嗜铬细胞症和亚克隆性肿瘤细胞群体或肿瘤内突变的异质性。在这里，我们提供的证据表明，TCC-UB中的染色细胞症过程是通过使用千碱基而不是兆碱基的DNA片段(我们称为“缝合器”)来修复这一过程的非同源末端连接所介导的。我们推测，在具有更复杂的基因型组的肿瘤中，一个潜在的统一主题是有缺陷的复制许可复合体。第二组(两个膀胱肿瘤)没有嗜铬症，一个更简单的基因，WT肿瘤蛋白P53，有相对较少的SNV(平均每兆基数5.9)，只有一个SV。没有证据表明肿瘤细胞是亚克隆性的。在这一组中，我们使用膀胱癌细胞系的临床前模型，研究了谷氨酸受体离子型N-甲基D-天冬氨酸基因的一个独特的SV(易位和扩增)，作为膀胱癌潜在的新治疗靶点。
Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.