乙肝病毒（HBV）慢性感染是肝细胞癌（HCC）主要原因。在乙肝致癌过程中，胞苷脱氨酶（APOBEC）通过诱导病毒和体细胞变异发挥炎-癌转化桥梁作用。本课题的关键科学问题是阐明慢性炎症刺激导致APOBEC与变异修复分子UNG和FHIT等之间功能失衡在HCC进化发育中的作用机理。拟采用大数据系统生物学分析、深度测序、促突变机制和多态功能研究、流行病学病例-对照研究和队列研究等方法，阐明炎症因子调控APOBEC与UNG/FHIT之间功能失衡机制；确定APOBEC驱动的体细胞变异、HBV变异和线粒体D环变异；阐明受变异激活的信号网络在促进HCC发生和再发的作用；探索三种分子启动子多态性、HBV变异、血清线粒体D环变异及网络分子表达与HCC发生的关联性；确定以上分子事件对HCC发生及复发的预测作用，探索预防HCC并改善预后新措施。对完善癌症进化发育理论、精准防控HCC具有重要意义。

Chronic infection with hepatitis B virus (HBV) is the prominent cause of hepatocellular carcinoma (HCC). During HBV-induced hepatocarcinogenesis, cytidine deaminases such as apolioprotein B mRNA-editing enzyme catalytic polypeptides (APOBECs) can bridge chronic inflammation and cancers via inducing viral and somatic mutations. This project is designed to elucidate the mechanisms by which APOBECs whose expression is trans-activated by proimflammatory factors promote the founctional dysequilibrium between APOBECs and uracil-DNA glycosylase (UNG) / fragile histidine triad (FHIT). Systemic biology assay for megadata, deep sequencing, mutagenesis assay of APOBECs, functional assay of the genetic polymorphisms as well as population-based epidemiological studies including case-control study and cohort studies will be sequencially applied in this study. The mechanisms of founctional dysequilibrium between APOBECs and UNG / FHIT, which is driven by proinflammatory factors, will be firstly elucidated. The major somatic mutations, HBV mutation signature, and mitochondrial DNA (mtDNA) mutation in the D-loop region that are induced by extrusive APOBECs will be serially identified. Proinflammatory molecules-reduced APOBECs-affected signaling networks will be constructed to elucidate their roles in promoting HCC occurrence and postoperative recurrence. We will evaluate the associations of the functional genetic polymorphisms in the putative regions of APOBECs, UNG, and FHIT, HBV mutations, serum mtDNA mutations, and inflammatory signaling molecules with the occurrence of HCC. We will identify the above molecular events that can predict the occurrence and recurrence of HBV-HCC, and develop specific prophylactic steps to reduce or postpone hepatocarcinogenesis and to improve the postoperative prognosis of HCC. This study will be of importance to consummate Cancer Evo-Dev theoretically and to precisely prevent and control HCC.