Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach.
Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach.
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DOI：
10.1371/journal.pgen.1003065
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lin B
中科院分区：
文献类型：
--
作者：
Ding D;Lou X;Hua D;Yu W;Li L;Wang J;Gao F;Zhao N;Ren G;Li L;Lin B
在大多数与乙肝病毒相关的肝细胞癌中发现了病毒DNA与宿主染色体的整合。在这里，我们设计了一种大规模锚定并行测序(MAP)方法，使用下一代测序来分离和测序乙肝病毒整合体。将MAP应用于40对与乙肝病毒相关的肝细胞癌组织(癌组织和癌旁组织)，我们识别了296个整合事件，对应于286个具有精确的乙肝病毒-人类DNA连接的独特整合位点(UIS)。乙肝病毒整合有利于17号染色体，并优先整合到人类转录单位。HBV靶向基因在GO方面表现丰富：cAMP代谢过程、T细胞分化和激活、转化生长因子β受体途径、ncRNA分解代谢过程、dsRNA断裂和细胞对dsRNA的反应。HBV靶向基因包括7个基因(PTPRJ、CNTN6、IL12B、MYOM1、FNDC3B、LRFN2、FN1)和7个基因(NRG3、MASP2、NELL1、LRP1B、ADAM21、NRXN1、FN1)和3个基因(PDE7A、PDE4B、PDE11A)和3个基因(PDE7A、PDE4B、PDE11A)。丰富的途径包括hsa04512(ECM-受体相互作用)、hsa04510(焦点黏附)和hsa04012(ErbB信号通路)。与癌旁组织相比，在癌组织中发现的整合事件较少，这表明在肝细胞癌的发展过程中存在克隆扩张模式。最后，我们通过整合确定了8个基因，包括纤维连接蛋白1(FN1)和端粒酶逆转录酶(TERT1)，两个已知的复发靶基因，以及其他新的靶基因，如SMAD家族成员5(Smad5)，磷酸酶和肌动蛋白调节因子4(PHACTR4)，RNA结合蛋白Fox-1同源物(秀丽线虫)1(RBFOX1)。结合最近发表的全基因组测序分析，我们又鉴定了14个乙肝复发靶基因，大大扩展了乙肝复发靶点列表。这项关于乙肝病毒整合事件的全球调查，加上最近发表的全基因组测序分析，进一步加深了我们对乙肝相关肝细胞癌的理解。在大多数相关的肝细胞癌(HCCs)中发现了乙肝病毒(HBV)整合到人的肝细胞中。在这里，我们借鉴高通量测序的最新进展，设计了一种高效且经济的方法，称为大规模锚定并行测序(MASS)方法，对40对与乙肝病毒相关的肝细胞癌组织(癌组织和癌旁组织)中的乙肝病毒整合事件进行了全球调查。我们确定了286个具有精确的乙肝病毒-人类DNA连接的独特整合位点(UIS)。我们在癌旁组织中发现了比在肝细胞癌组织中更高数量的乙肝病毒整合事件，这表明在肝细胞癌发展过程中存在克隆性的扩张过程。我们还发现，纤维连接蛋白及其相关基因(含有纤维连接蛋白III型折叠结构域的基因)经常成为乙肝病毒的靶标。纤维连接蛋白是一种由肝细胞大量产生的蛋白质，也是细胞外基质的连接物。我们的发现可能提示纤维连接蛋白和相关细胞基质的破坏在乙肝病毒相关性肝癌中的作用。我们还发现了14个新的乙肝复发靶点基因，大大扩展了乙肝复发靶点列表。这项研究将大大增加我们对肝细胞癌发生发展的了解。
Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV)–related hepatocellular carcinomas (HCCs). Here we devised a massive anchored parallel sequencing (MAPS) method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV–related HCC tissues (cancer and adjacent tissues), we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs) with precise HBV–Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1) containing IPR003961 (Fibronectin, type III domain), 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1) containing IPR013032 (EGF-like region, conserved site), and three genes (PDE7A, PDE4B, PDE11A) containing IPR002073 (3′, 5′-cyclic-nucleotide phosphodiesterase). Enriched pathways include hsa04512 (ECM-receptor interaction), hsa04510 (Focal adhesion), and hsa04012 (ErbB signaling pathway). Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1) and telomerase reverse transcriptase (TERT1), two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5), phosphatase and actin regulator 4 (PHACTR4), and RNA binding protein fox-1 homolog (C. elegans) 1 (RBFOX1). Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This global survey of HBV integration events, together with recently published whole-genome sequencing analyses, furthered our understanding of the HBV–related HCC. Integration of the hepatitis B virus (HBV) into the human liver cells was found in most of the related hepatocellular carcinomas (HCCs). Here, taking the recent advances in high-throughput sequencing, we devised an efficient and cost-effective method that we named massive anchored parallel sequencing (MAPS) method, to conduct a global survey of HBV integration events in 40 pairs of HBV–related HCC tissues (cancer and adjacent tissues). We identified 286 unique integration sites (UISs) with precise HBV–Human DNA junctions. We identified a higher number of HBV integration events in cancer adjacent tissues than in HCC tissues, suggesting a clonal expansion process during HCC development. We also found that fibronectin and its related genes (fibronectin type III-like fold domain containing genes) were frequently targeted by HBV. Fibronectin is a protein produced abundantly by the liver cells and also serves as a linker in the extracellular matrix. Our findings might suggest a role for the disruption of fibronectin and associated cellular matrix in HBV related liver cancers. We also identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This study would add significantly to our understanding of HCC development.
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影响因子：
64.8
作者：
DEJEAN, A;BOUGUELERET, L;TIOLLAIS, P
通讯作者：
TIOLLAIS, P
影响因子：
8
作者：
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作者：
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通讯作者：
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影响因子：
7
作者：
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通讯作者：
Zhang, Zemin
影响因子：
8
作者：
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通讯作者：
Dejean, A