Yang Xiaobo, Wu Liangcai, Lin Jianzhen, Wang Anqiang, Wan Xueshuai, Wu Yan, Robson Simon C, Sang Xinting, Zhao Haitao
Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China.
Department of Medicine, Liver Center and The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Int J Cancer. 2017 Mar 15;140(6):1324-1330. doi: 10.1002/ijc.30547.
Infection by the hepatitis B virus (HBV) is one of the main etiologies of hepatocellular carcinoma (HCC). During chronic infection, HBV DNA can integrate into the human genome, and this has been postulated as a possible mechanism of HBV-induced HCC. In this study we used 2199 HBV integration sites from Dr.VIS v2.0 and mapped them to the human genome (hg19) to obtain viral integration sites (VIS) related to protein-coding and non-protein-coding genes. In total, we found 1,377 and 767 VIS within close proximity to protein coding genes and noncoding genes, respectively. Genes affected more than two times included 23.1% of protein-coding genes and 24.7% of long noncoding RNAs (lncRNA). Only 4.8% of VIS were shared between HCC and non-tumor tissues. HBV integrations were more common in chromosomes 5, 8, 10, and 19 in HCC tissue and chromosomes 1 and 2 in non-tumorous tissue. The number of integration sites on each chromosome correlated with the number of fragile sites in non-tumorous tissue but not in HCC tissue. Functional enrichment analysis of the protein-coding genes containing or in close proximity to HBV integration sites in HCC tissue showed an enrichment of cancer related gene ontology terms. Additionally, the most frequently associated lncRNA genes were related to telomere maintenance, protein modification processes, and chromosome localization. Thus, HBV may have preferred integration sites in the human genome that serve a critical role in HCC development. These results show that HCC treatment may benefit from the development of next generation anti-viral therapies.
乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要病因之一。在慢性感染期间，HBV DNA可整合到人类基因组中，这被认为是HBV诱发HCC的一种可能机制。在本研究中，我们使用了来自Dr.VIS v2.0的2199个HBV整合位点，并将它们映射到人类基因组（hg19）上，以获得与蛋白质编码基因和非蛋白质编码基因相关的病毒整合位点（VIS）。我们总共在靠近蛋白质编码基因和非编码基因的区域分别发现了1377个和767个VIS。受影响超过两次的基因包括23.1%的蛋白质编码基因和24.7%的长链非编码RNA（lncRNA）。只有4.8%的VIS在HCC和非肿瘤组织之间共享。HBV整合在HCC组织的5号、8号、10号和19号染色体以及非肿瘤组织的1号和2号染色体中更为常见。每条染色体上的整合位点数量与非肿瘤组织中的脆性位点数量相关，但与HCC组织中的脆性位点数量无关。对HCC组织中包含或靠近HBV整合位点的蛋白质编码基因进行功能富集分析，结果显示与癌症相关的基因本体术语富集。此外，最常相关的lncRNA基因与端粒维持、蛋白质修饰过程和染色体定位有关。因此，HBV可能在人类基因组中有优先整合位点，这些位点在HCC发展中起关键作用。这些结果表明，HCC治疗可能受益于下一代抗病毒疗法的开发。
