Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.
Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.
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DOI：
10.1136/gutjnl-2020-323153
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发表时间：
2022-03
期刊：
影响因子：
24.5
通讯作者：
Zucman-Rossi J
中科院分区：
文献类型：
--
作者：
Péneau C;Imbeaud S;La Bella T;Hirsch TZ;Caruso S;Calderaro J;Paradis V;Blanc JF;Letouzé E;Nault JC;Amaddeo G;Zucman-Rossi J
乙型肝炎病毒感染是全世界肝细胞癌（HCC）的主要危险因素。乙型肝炎病毒通过整合到人类基因组中直接驱动致癌。本研究旨在精确描述 HBV 整合与病毒和宿主基因组学以及临床特征的关系。建立了一个新的管道，对来自法国队列的 177 名主要来自欧洲和非洲的患者的肿瘤和非肿瘤肝组织进行病毒捕获。每个整合事件的克隆性由整合序列的定位、方向和内容决定。在三个选定的肿瘤中，使用长读长测序或 Bionano 全基因组作图重建了复杂的整合。在非肿瘤组织中更频繁地检测到复制的 HBV DNA，并且与更多数量的非克隆整合相关。在 HCC 中，HBV 整合的克隆选择与致癌过程中的两种不同机制有关。首先，病毒增强子在癌症驱动基因附近的整合可能导致癌基因的强烈过度表达。其次，我们发现 HBV 整合位点频繁的染色体重排导致癌症驱动基因（TERT、TP53、MYC）发生远距离改变。此外，HBV 整合具有直接的临床意义，因为年轻患者会发生大量插入的 HCC，且预后较差。乙型肝炎病毒在肝组织中整合的深入表征凸显了参与肝癌发生的新的乙型肝炎病毒相关驱动机制。 HBV 整合具有多种直接致癌后果，这对于 HBV 感染患者的随访仍然是一个重要挑战。
Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features. A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping. Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis. Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.
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DOI：
10.20517/2394-5079.2016.05
发表时间：
2016
期刊：
Hepatoma research
影响因子：
--
作者：
Lamontagne RJ;Bagga S;Bouchard MJ
通讯作者：
Bouchard MJ
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
25.7
作者：
Li, Xiaojun;Zhang, Jiangbo;Lu, Fengmin
通讯作者：
Lu, Fengmin
影响因子：
13.5
作者：
Hosaka, Tetsuya;Suzuki, Fumitaka;Kumada, Hiromitsu
通讯作者：
Kumada, Hiromitsu