Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection
Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection
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DOI：
10.1158/1078-0432.ccr-18-4041
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发表时间：
2019-10-15
影响因子：
11.5
通讯作者：
Aburatani, Hiroyuki
中科院分区：
文献类型：
--
作者：
Tatsuno, Kenji;Midorikawa, Yutaka;Aburatani, Hiroyuki
目的：在慢性乙肝患者中，乙肝病毒DNA经常整合到肝细胞癌的基因组中，但在乙肝病毒消失后，患者体内整合的频率尚不清楚。实验设计：应用病毒捕获测序技术，对73例既往无丙型肝炎病毒感染者和81例慢性乙肝患者的肝组织标本进行病毒捕获测序。结果：在既往无丙型肝炎病毒感染者11例(15.0%)和慢性乙肝患者61例(75.3%)中发现了克隆性乙肝病毒整合事件。有几个驱动基因是乙肝病毒共同的靶点，导致这些基因的转录激活；TERT[四个(5.4%)比15(18.5%)]，KMT2B[两个(2.7%)比五个(6.1%)]，CCNE1[零比一(1.2%)]，Ccna2[零比一(1.2%)]。相反，CCNE1和Ccna2分别只在先前的乙肝病毒中被AAV2靶向。在肝脏样本中，在慢性乙肝中，乙肝病毒基因组反复整合到纤维化相关基因FN1、HS6ST3、KNG1和ROCK1中。结论：尽管乙肝表面抗原血清被清除，但乙肝病毒或AAV2基因整合的患者并不罕见，因此，此类患者有发生肝细胞癌的风险。
Purpose: Hepatitis B viral (HBV) DNA is frequently integrated into the genomes of hepatocellular carcinoma (HCC) in patients with chronic HBV infection (chronic HBV, hereafter), whereas the frequency of HBV integration in patients after the disappearance of HBV (prior HBV, hereafter) has yet to be determined. This study aimed to detect integration of HBV and adeno-associated virus type 2 (AAV2) into the human genome as a possible oncogenic event.Experimental Design: Virome capture sequencing was performed, using HCC and liver samples obtained from 243 patients, including 73 with prior HBV without hepatitis C viral (HCV) infection and 81 with chronic HBV.Results: Clonal HBV integration events were identified in 11 (15.0%) cases of prior HBV without HCV and 61 (75.3%) cases of chronic HBV (P < 0.001). Several driver genes were commonly targeted by HBV, leading to transcriptional activation of these genes; TERT [four (5.4%) vs. 15 (18.5%)], KMT2B [two (2.7%) vs. five (6.1%)], CCNE1 [zero vs. one (1.2%)], CCNA2 [zero vs. one (1.2%)]. Conversely, CCNE1 and CCNA2 were, respectively, targeted by AAV2 only in prior HBV. In liver samples, HBV genome recurrently integrated into fibrosis-related genes FN1, HS6ST3, KNG1, and ROCK1 in chronic HBV. There was not history of alcohol abuse and 3 patients with a history of nucleoside analogue treatment for HBV in 8 prior HBV with driver gene integration.Conclusions: Despite the seroclearance of hepatitis B surface antigen, HBV or AAV2 integration in prior HBV was not rare; therefore, such patients are at risk of developing HCC.