肝癌患者糖脂代谢基因突变及术后生存预测模型的研究

发布时间：2018-08-20 09:54

【摘要】：目的:原发性肝癌是最常见的恶性肿瘤之一,90%以上的原发性肝癌为肝细胞癌(hepatocellular carcinoma,HCC;以下简称肝癌)。在人类常见的恶性肿瘤中,肝癌的发病率位居第5位,死亡率位居第3位。我国是肝癌高发国家,每年新发病例约30万左右,约占全球肝癌新发病例的半数以上。肝癌具有恶性程度高、病程进展迅速、易复发和转移的特点。肝癌的治疗方法虽然有多种,但总体疗效仍不理想。并且手术预后情况较差,总体术后5年复发率仍高达60%以上。肝癌更多地发生在肝硬化基础上,是典型的长期慢性炎症基础上的恶性肿瘤,多数患者就诊时已为中晚期,手术切除的不到20%,适合局部消融患者有限。因此肝癌仍是目前临床上治疗效果最差的肿瘤之一。考虑肿瘤是一种多基因病,肝癌属于多因素复杂疾病,经过多个阶段的发展而产生的。据已有的研究推测肝癌的发生可能与机体的易感基因密切相关。近年来代谢异常与肿瘤的关系逐渐被科研人员所重视,新疆是代谢因素高流行区,且本地区肝癌的发病率又具有一定特点,发现肝癌的代谢易感基因,不仅有助于深入解析肝癌的发病机制,而且能为个体罹患肝癌的风险预测、早期预防、个体化医疗及新型高效药物的筛选提供理论依据和生物靶标;对于肝癌根治术预后较差的现况,企盼建立HCC切除术5年生存情况危险指数(PI)预测模型,并验证该模型在预测HCC切除术5年内死亡风险的准确性。方法:本研究以自2009年10月至2013年9月四年间在新疆医科大学第一附属医院入院的肝硬化及肝癌患者为研究对象,肝硬化患者为对照组,病例组为肝硬化基础上的肝细胞癌患者,采用病例-对照研究方法,选取tagSNP利用SnaPshot方法检测糖脂代谢基因,目的在于从代谢角度研究在已知的肝癌风险因素的前提下,评价糖脂代谢基因异常对肝硬化癌变发生的风险相关性;并对自2007年10月至2010年12月在新疆医科大学第一附属医院收治的行切除根治手术治疗的肝癌患者作为研究对象,对201例的临床资料进行了回顾性地分析,运用统计学方法建立乙肝相关肝癌术后风险指数模型,以该模型预测乙型相关肝癌患者根治术后5年生存风险的相关因素。结果:本研究第一部分检测与糖尿病风险相关的GCKR基因的三个标签位点的基因型在两组间分布的差异情况,以期研究与糖尿病相关的GCKR(葡萄糖激酶调节蛋白)基因多态性与肝硬化癌变的风险相关性,统计结果表明该基因多态性在本研究人群中与肝硬化癌变无相关性;本研究的第二部分选取tagSNP后利用SnaPshot方法检测PNPLA3(类淀粉磷脂酶区域3蛋白)基因的10个标签位点的基因型分布在两组间的差异情况,以期研究与非酒精性脂肪性肝病和非酒精性脂肪型肝炎发病风险相关的PNPLA3基因多态性与肝硬化癌变是否具有风险相关性,结果表明该基因多态性在本研究人群中与肝硬化癌变无相关性;基于该基因对于肝脏脂肪变性的风险相关性研究已有报道,仍可作为今后肝脏脂肪变性的研究方向。但在本研究中该位点不具有在促使肝硬化患者致癌的风险性。第三部分是基于肝癌切除术后患者生存状况的不理想现状,本地区乙型肝炎病毒携带者占较大比例,初建了PI模型及临界值3.38作为对乙型肝炎相关肝癌患者术后生存情况进行评估预测,对于选用合理的治疗方法提高患者生存率有一定的临床参考价值。结论:本研究所检测的两个糖脂代谢相关基因多态性可能与本地区研究人群的肝硬化癌变风险无关;PI模型有助于预测肝癌根治术患者5年内死亡风险程度,并提供明确的数学模型及临界值;对乙型肝炎相关肝癌患者术后生存情况的预测评估价值较高,对于选用合理的治疗方法以提高患者生存率具有重要的临床意义。
[Abstract]:Objective: Primary liver cancer is one of the most common malignant tumors, more than 90% of which are hepatocellular carcinoma (HCC). Hepatocellular carcinoma (HCC) has the characteristics of high malignancy, rapid progression, easy recurrence and metastasis. Although there are many treatments for HCC, the overall curative effect is still unsatisfactory. On the basis of this, it is a typical malignant tumor with long-term chronic inflammation. Most of the patients are in the middle and advanced stage, less than 20% of them have been resected surgically, which is suitable for local ablation. In recent years, the relationship between metabolic abnormalities and tumors has been paid more and more attention by researchers. Xinjiang is a high prevalence area of metabolic factors, and the incidence of hepatocellular carcinoma in this region has certain characteristics. The metabolic susceptibility base of hepatocellular carcinoma has been found. It not only helps to analyze the pathogenesis of HCC, but also provides theoretical basis and biological targets for individual risk prediction, early prevention, individualized medical treatment and screening of new and high-effective drugs. Methods: From October 2009 to September 2013, patients with cirrhosis and hepatocellular carcinoma admitted to the First Affiliated Hospital of Xinjiang Medical University were selected as the study subjects, patients with cirrhosis as the control group and patients with hepatocellular carcinoma on the basis of cirrhosis as the case group. Tag SNP was selected to detect the glycolipid metabolism genes by SnaPshot method. The purpose of this study was to evaluate the relationship between the abnormal glycolipid metabolism genes and the risk of liver cirrhosis carcinogenesis on the premise of the known risk factors of liver cancer from the metabolic point of view. The clinical data of 201 patients with hepatocellular carcinoma who underwent resection and radical operation in a Affiliated Hospital were retrospectively analyzed. The risk index model of hepatitis B related hepatocellular carcinoma was established by statistical method. The model was used to predict the risk factors of survival of patients with hepatocellular carcinoma after radical operation for 5 years. In the first part of this study, genotypes of three marker loci of the GCKR gene associated with diabetes mellitus were detected in the two groups, in order to study the association between the polymorphism of the GCKR gene associated with diabetes mellitus and the risk of liver cirrhosis and carcinogenesis. In the second part of this study, we selected tagSNP and used SnaPshot method to detect the genotype distribution of 10 tag loci of PNPLA3 (amyloid phospholipase region 3 protein) gene between the two groups in order to study the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic fatty hepatitis. Risk-related polymorphisms of the PNPLA3 gene are not associated with liver cirrhosis carcinogenesis in this study population. Risk-related studies based on this gene for liver steatosis have been reported and can be used as a research direction in the future. The third part is based on the unsatisfactory living condition of the patients after hepatectomy. The hepatitis B virus carriers account for a large proportion in this area. The PI model and the critical value of 3.38 were established to evaluate the survival of the patients with hepatitis B-related liver cancer after hepatectomy. Conclusion: The two glycolipid metabolism-related gene polymorphisms detected in this study may not be associated with the risk of cirrhosis and canceration in the local population; PI model is helpful in predicting the risk of death in patients undergoing radical hepatectomy within 5 years, and mention It is of great value to predict and evaluate the survival of patients with hepatitis B-related liver cancer after operation, and it has important clinical significance to select reasonable treatment methods to improve the survival rate of patients.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.7

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