The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma.
The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma.
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EBV 和感染胃组织从前驱病变到癌的基因组结构
DOI：
10.1186/s13073-021-00963-2
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发表时间：
2021-09-07
期刊：
影响因子：
12.3
通讯作者：
Zhong Q
中科院分区：
文献类型：
--
作者：
Chen ZH;Yan SM;Chen XX;Zhang Q;Liu SX;Liu Y;Luo YL;Zhang C;Xu M;Zhao YF;Huang LY;Liu BL;Xia TL;Xu DZ;Liang Y;Chen YM;Wang W;Yuan SQ;Zhang HZ;Yun JP;Zhai WW;Zeng MS;Bai F;Zhong Q
EB病毒(EBV)相关性胃癌(EBVaGCs)具有独特的分子特征，但EBVaGCs的肿瘤发生机制以及EBV在这一过程中所起的作用尚不清楚。方法我们对来自同一患者(n=25)的多个样本(n=123)进行了全外显子测序、EBV基因组测序和全基因组测序，包括唾液样本和从形态正常的上皮组织到异型增生和EBVaGCs的不同组织学阶段。我们比较了EBVaGCs和它们的前驱病变之间的基因组图谱，并追踪了每个患者的克隆进化。我们还从不同组织类型的样本中分析了EBV的基因组序列。在体外实验和体内移植实验中，通过四甲基偶氮唑盐比色法、半数抑制浓度和集落形成分析，证实了促进肿瘤演变的关键分子事件。结果我们的分析发现，从正常组织和低度异型增生(LD)到高度异型增生(HD)和EBVaGCs，突变负担和EBV载量增加，并且EBVaGCs的致癌扩增发生得较晚。有趣的是，在每个患者中，EBVaGCs和HDs是单克隆性的，含有单一毒株来源的EBV，但唾液或正常组织/LDS的EBV毒株与EBVaGCs不同。与前驱病变相比，肿瘤细胞启动子区域的甲基化增加，而EBV呈现一致的超甲基化。在EBV感染的细胞中发现了针对PI3K-Akt和Wnt通路的显性改变。这两条途径在EBV阳性肿瘤细胞中的联合抑制证实了它们的协同作用。结论我们描绘了EBVaGCs(Epi)基因组的进化过程，揭示了EBV在肿瘤和正常组织部位之间广泛的基因组多样性，并证实了EBVaGCs中PI3K和Wnt通路的协同激活，为该病的治疗提供了新的潜在策略。
BackgroundEpstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood.MethodsWe applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n= 123) derived from the same patients (n= 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assayin vitroexperiments andin vivoxenograft experiments.ResultsOur analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function.ConclusionsWe portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.
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影响因子：
5.4
作者：
Midgley, RS;Bell, AI;Rickinson, AB
通讯作者：
Rickinson, AB
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
通过多区域全外显子组测序对食管鳞状细胞癌及其癌前病变进行基因组比较。
影响因子：
16.6
作者：
Chen XX;Zhong Q;Liu Y;Yan SM;Chen ZH;Jin SZ;Xia TL;Li RY;Zhou AJ;Su Z;Huang YH;Huang QT;Huang LY;Zhang X;Zhao YN;Yun JP;Wu QL;Lin DX;Bai F;Zeng MS
通讯作者：
Zeng MS
影响因子：
50.3
作者：
Mazor T;Pankov A;Johnson BE;Hong C;Hamilton EG;Bell RJA;Smirnov IV;Reis GF;Phillips JJ;Barnes MJ;Idbaih A;Alentorn A;Kloezeman JJ;Lamfers MLM;Bollen AW;Taylor BS;Molinaro AM;Olshen AB;Chang SM;Song JS;Costello JF
通讯作者：
Costello JF
影响因子：
5.8
作者：
Akalin, Altuna;Franke, Vedran;Schuebeler, Dirk
通讯作者：
Schuebeler, Dirk