慢性乙型肝炎患者宿主基因和HBV准种复杂度对肝癌发生的影响及早期预测风险模型的研究

Global multicenter clinical studies have proven that hepatitis B virus (HBV) infection factors, including high level of viral load, genotype C and virus mutations, are risk factors for hepatocellular carcinoma (HCC). Meanwhile host genetic background factors, including Family history of HCC and host gene mutations, are also risk factors for HCC. Large-scale clinical studies have shown that HBV infection and host genetic background have synergistic effects on risk for incident HCC. The reason might be the interaction between HBV mutations and host single nucleotide polymorphism (SNP). Here, we hypothesize a synergistic interaction between f HBV mutations and host mutations in their joint association in increasing HCC risk, while they are both risk factors for HCC. We will perform human whole genome sequencing and hepatitis B virus full-length next-generation sequencing to identify HBV mutations and host mutations in relation to the risk of HCC. The synergism of them on the increased risk of cancer will be examined. Hepatocarcinoma risk model will be established to estimate the risk of HCC susceptibility risk of chronic hepatitis B patients from HBV variants and host genetic background. Supposedly, our finding can provide theoretical basis to regular follow-up, early prevention and early diagnosis of the susceptible population of HBV-related HCC and apply to precision medicine.

临床研究说明乙型肝炎病毒（HBV）感染，包括高水平病毒载量、基因型C型、病毒变异，是肝细胞癌（HCC）发生的危险因素，同时宿主遗传背景，包括肝癌家族史、宿主基因变异，也是HCC发生的危险因素。大型临床研究表明，HBV感染和宿主遗传背景对HCC发生有显著的协同作用，这可能是由于HBV变异与宿主SNP之间的相互作用。由此我们提出假说：HBV变异和宿主基因变异在各自促进HCC发生的基础上，其相互作用会对HCC的发生产生协同作用。我们将采用人类全基因组测序和HBV全长二代测序的方法，筛选出与肝癌易感相关的宿主基因变异和HBV突变，检验两者对肝癌发生是否有协同作用，并在此基础上建立肝癌易感风险模型，从宿主遗传背景和HBV突变两方面共同评估慢性乙型肝炎患者的肝癌易感风险，为肝癌易感人群的积极随访和早期预防、早期诊断提供科学依据，实现精准医疗。

在慢性乙型肝炎患者中，肝癌家族史所代表的宿主遗传基因和HBV准种所代表的病毒变异能共同促进肝炎向肝硬化、肝癌进展，这提示两者在肝癌发生机制上有协同作用，可以将此应用在肝癌易感风险预测模型上，提高肝癌预测模型的准确性。.我们在研究中发现，慢性乙型肝炎患者的血清中的免疫球蛋白选择性的增高以及高Th-17细胞水平（>5.9%）可以作为一个不良预后的指示因素。肝硬化及肝癌的HBV准种异质性比慢性乙型肝炎的高，可能与感染时间、病毒准种的相互作用以及免疫压力有关。在慢性乙型肝炎患者中，有肝癌家族史者较无肝癌家族史者核苷酸变异率高，更接近肝硬化及肝癌的核苷酸变异率，这可能与宿主遗传背景对HBV造成的选择压力、初始感染病毒异质性高、病毒反复感染等因素有关。上述研究结果发表SCI论文6篇（均标注），博士研究生5名和硕士研究生1名。