Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer
Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer
复制标题
全基因组测序揭示了胃癌中新的串联复制热点和预后突变特征
DOI：
10.1038/s41467-019-09644-6
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发表时间：
2019-05-02
影响因子：
16.6
通讯作者：
Lu, Youyong
中科院分区：
文献类型：
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作者：
Xing, Rui;Zhou, Yong;Lu, Youyong
基因组特征的全基因组分析可能会揭示胃癌（GC）肿瘤发生的新机制。在这里，我们通过168个GC的全基因组测序分析了结构变异（SV）和突变特征。我们的数据表明，复杂的SV在GC中的操作，这导致高水平的癌基因扩增的不同模型。我们发现不同个体间存在不同比例的串联重复（TD），并确定了24个TD热点，涉及CCND1、ERBB2和MYC等成熟的癌症基因。具体而言，我们提名了一个新的热点，涉及ZFP 36 L2的超级增强子，该增强子存在于来自不同队列的约10%的GC中，其致癌作用通过实验数据进一步证实。此外，我们的数据揭示了一个突变特征，特别是发生在非编码区，在具有钙粘蛋白11突变的肿瘤中显著富集，并与不良预后相关。总的来说，我们的数据表明，TDs可能是癌症基因激活的一个重要机制，并为分层提供了一个新的签名。
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such asCCND1, ERBB2andMYC. Specifically, we nominate a novel hotspot involving the super-enhancer ofZFP36L2presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors withcadherin 1mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.