Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma.
Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma.
复制标题
全基因组测序揭示了食管鳞状细胞癌结构变异的多种模型。
DOI：
10.1016/j.ajhg.2015.12.013
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发表时间：
2016-02-04
影响因子：
9.8
通讯作者：
Cui Y
中科院分区：
文献类型：
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作者：
Cheng C;Zhou Y;Li H;Xiong T;Li S;Bi Y;Kong P;Wang F;Cui H;Li Y;Fang X;Yan T;Li Y;Wang J;Yang B;Zhang L;Jia Z;Song B;Hu X;Yang J;Qiu H;Zhang G;Liu J;Xu E;Shi R;Zhang Y;Liu H;He C;Zhao Z;Qian Y;Rong R;Han Z;Zhang Y;Luo W;Wang J;Peng S;Yang X;Li X;Li L;Fang H;Liu X;Ma L;Chen Y;Guo S;Chen X;Xi Y;Li G;Liang J;Yang X;Guo J;Jia J;Li Q;Cheng X;Zhan Q;Cui Y
全面鉴定体细胞结构变异（SV）并了解其在癌症中的突变机制可能有助于理解生物学差异，并有助于确定新的治疗靶点。不幸的是，在整个基因组中复杂SV的特征和食管鳞状细胞癌（ESCC）的突变机制在很大程度上是不清楚的。为了定义ESCC中体细胞SV、受影响的靶基因及其潜在机制的全面目录，我们使用Meerkat算法重新分析了来自31个ESCC的全基因组测序（WGS）数据，以预测体细胞SV和Patchwork以确定拷贝数变化。我们发现缺失和易位与NHEJ和alt-EJ签名作为主要的SV类型，和16%的缺失是复杂的缺失。SV经常导致癌症相关基因的破坏（例如，CDKN 2A和NOTCH 1）具有不同的突变机制。此外，chromothripsis，kataegis和断裂融合桥（BFB）被确定为有助于发生在55%的ESCC中的局部错误排列的染色体。这些基因组灾难导致癌基因的扩增，通过染色体萎缩衍生的双微染色体形成（例如，FGFR 1和LETM 2）或BFB影响的染色体（例如，CCND 1、EGFR、ERBB 2、MMPs和MYC），约30%的ESCC携带BFB来源的CCND 1扩增。此外，对拷贝数改变的分析揭示了高频率的全基因组复制（WGD）和CDCA 7的复发性局灶性扩增，这可能是ESCC中潜在的癌基因。我们的研究结果揭示了分子缺陷，如chromothripsis和BFB在恶性转化的食管鳞癌和演示不同的模型SV衍生的靶基因在食管鳞癌。这些全基因组SV谱及其潜在机制为ESCC提供了预防、诊断和治疗意义。
Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.