大规模双向队列人群中基于miR-375构建HBV相关性肝癌发病早期预测模型

The mortality of hepatocellutar carcinoma (HCC) ranks second among all the tumors in China. And the most important reason of liver cancer is hepatitis B virus (HBV) infection. Since most patients have missed the best treatment time, our country died more than half of those in the world. Therefore, it is very important to realize the early prediction of HCC. This study is based on the early study which is the expression and clinical significance of miR-375 in the process of HCC (including histological, cytological and case-control study). Then, based on the study of HBV prevention and control of demonstration areas in wuwei, we conduct ambispective cohort study and nested case-control study. We continuously observe the disease progression of those people with high risk of HCC and detect the expression level of miR-375 in the serum of the HBV carriers, the patients of chronic hepatitis B infection and HBV-related HCC. We hope to clear of the incidence rate and the risk factors of HCC. Then analyze the correlation between the miR-375 levels and the HBV serological markers, clinical features and prognosis. And we also evaluate the value of miR-375 in early diagnosis of HCC. Predictive model for HBV related HCC will be constructed and validated by two ways: combination with principal components analysis and logistic regression and combination with classification tree model and logistic regression. The study will provide valuable clues for the early prediction of HBV-related HCC which is helpful to screen and early diagnose those people with high risk of HCC.

肝癌死亡率位居我国肿瘤第2位，HBV感染是我国肝癌发生最主要原因。由于大部分患者诊断时已错过最佳治疗时机，我国死亡病例超过全球半数。因此实现肝癌的早期预测对减少病例死亡具有重要意义。本课题以前期对miR-375在肝癌疾病进程中的表达和临床意义的研究结果（组织、细胞学和病例对照研究）为基础，以甘肃武威乙肝示范区为研究现场，开展双向队列研究及巢式病例对照研究。对肝癌高危人群疾病进程连续性观察，从乙肝携带者、慢乙肝到肝癌发展中血清miR-375的表达水平变化，计算肝癌发病密度，分析肝癌发生的危险因素，探讨miR-375与临床特征、乙肝感染指标、预后的相关性，并评价其作为肝癌早期诊断指标的价值。采用两种方式，主成分分析与Logistic结合，分类树模型和logistic联合，构建肝癌发病早期预测模型，并验证。这将为乙肝相关性肝癌疾病进展的早期预测提供重要线索，有助于肝癌高危人群的筛选和早期诊断。

HBV感染是我国肝癌发生最主要原因，由于大部分患者诊断时已错过最佳治疗时机，我国死亡病例超过全球半数。因此实现肝癌的早期预测对减少病例死亡具有重要意义。本课题在武威市肿瘤医院收集HBV慢性感染者与携带者3909例组建队列，进行流行病学调查及随访。主要研究结果：①队列人群HBsAg转变：93.3%始终保持HbsAg+，1.5%始终保持HbsAg-，1.8%阴转阳，3.4%阳转阴。HBeAg转变：14.3%始终保持HBeAg+，76.8%始终保持HBeAg-，2.6%阴转阳，6.3%阳转阴。HBV DNA水平：25.1%降低，10.8%明显升高。LSM水平转变：17.4%降低，5.8%明显升高。②健康对照组的miR-375表达量最高，慢性乙型肝炎组、乙肝肝硬化组和HBV-HCC组的血清miR-375水平依次降低。血清miR-375水平与ALT、AST、HbeAg、HBV DNA、肿瘤数目、癌栓、肝硬化、AFP、CEA存在相关性。③血清miR-375预测HBV-HCC具有较高灵敏度（91.1%）和特异度（79.8%），AUC为0.901（95%CI：0.856~0.946），将其与AFP、肝硬度值进行比较，miR-375诊断效能优于AFP与肝硬度值。联合预测结果显示，miR-375+AFP最好：AUC为0.909（95%CI：0.868-0.950），灵敏度91.1%，特异度78.8%。④评价血清miR-375在HCC-TACE术后患者预后评估中的价值：单用miR-375，AUC为0.835（0.676-0.941），灵敏度89.0%，特异度68.8%，优于AFP、Fibroscan和CEA。miR-375+AFP分别与肝硬度值、CEA三者联合预测预后的结果显示，miR-375+AFP+肝硬度值效能最高，AUC为0.848（0.736-0.921），灵敏度为92.1%，特异度为77.2%。⑤分析HBV-HCC组与HBV非肝癌组患者临床指标的差异，结果显示两组的家族史、B 超、HBeAg，HBcAb、ALT、AST、胆红素、γ谷氨酰转肽酶、白蛋白、AFP、肝硬度值及miR-375水平均有显著差异，并以乙肝家族史、AST、miR-375以及AFP水平建立HBV-HCC预测模型。研究结果将为肝癌疾病进展的早期预测提供重要线索，有助于肝癌高危人群的筛选和早期诊断。