血清四种microRNAs联合诊断早期原发性肝细胞肝癌的初步分析

发布时间：2018-05-07 14:55

本文选题：原发性肝癌 + 微小RNA　；参考：《天津医科大学》2015年硕士论文

【摘要】：目的循环肿瘤标志物有助于诊断早期原发性肝细胞癌(hepatocellular carcinoma,HCC),然而目前辅助临床诊断的HCC标志物并不令人满意,主要问题在于其准确性、灵敏性和特异性均较低。循环微小RNA(microRNAs,miRNAs)的研究方向带来了新的思路。本研究探讨mi R-125b、miR-223、miR-27a和mi R-26a作为HCC血清标志物的可能性和临床价值。通过联合检测来提高筛查诊断早期HCC的准确性、灵敏性和特异性。方法选取天津医科大学肿瘤医院90例原发性乙肝肝炎病毒(hepatitis B virus,HBV)相关的HCC患者为实验组(HCC组),30例健康志愿者(健康对照组)和30例HBV患者(HBV组)为对照组。分别采用巴塞罗那分期(Barcelona Clinic Liver Cancer,BCLC)和TNM(Tumor-node-etastasis)分期系统定义早期HCC患者。通过实时荧光定量PCR(quantitative real-time polymerase chain reaction,qRT-PCR)检测各组的血清miR-125b、miR-223、mi R-27a和miR-26a,并采用2-△△Ct进行mi RNAs相对表达量分析。利用R 3.1软件完成统计分析。单一指标筛查之后,通过logistic回归模型实现多指标联合诊断HCC和早期HCC,并应用于健康对照组、HBV组,以及非癌症组(健康对照组+HBV组)中进行受试者工作曲线(receiver operating characteristic curve,ROC)分析,确定各指标诊断的灵敏性和特异性,并由Bootstrap确定构建模型的稳定性。结果1.分别与健康对照组和HBV组相比,HCC患者血清中的miR-125b、miR-223、miR-27a和miR-26a相对表达水平降低(P0.0001)。2.以非癌症组为对照,单一mi RNA筛查诊断HCC效能最好的是miR-27a,AUC为0.849,灵敏性为73.0%,特异性为85.0%;联合四种miRNAs诊断的AUC提高为0.870,灵敏性提高为79.8%,特异性为81.7%。以健康对照组为对照,单一miRNA筛查诊断HCC效能最好的是miR-27a,AUC为0.930,灵敏性为94.0%,特异性为77.0%;联合四种miRNAs诊断的AUC提高为0.970,灵敏性为94.0%,特异性提高为90.0%。以HBV组为对照,单一miRNA筛查诊断HCC效能最好的是miR-223,AUC为0.826,灵敏性为73.0%,特异性为83.3%;联合四种miRNAs诊断的AUC提高为0.833,灵敏性提高为82.0%,特异性为76.7%。3.基于BCLC分期,以非癌症组为对照,单一miRNA筛查诊断早期HCC效能最好的是miR-223,AUC为0.793,灵敏性为70.4%,特异性为81.7%;联合四种miRNAs诊断的AUC提高为0.843,灵敏性提高为81.5%,特异性为75.0%。以健康对照组为对照,单一miRNA筛查诊断早期HCC效能最好的是miR-27a,AUC为0.920,灵敏性为81.0%,特异性为90.0%;联合四种miRNAs诊断的AUC提高为0.960,灵敏性为80.0%,特异性提高为100.0%。以HBV组为对照,单一miRNA筛查诊断早期HCC效能最好的是miR-223,AUC为0.809,灵敏性为74.1%,特异性为83.3%;联合四种miRNAs诊断的AUC提高为0.812,灵敏性为70.4%,特异性为83.3%。4.基于TNM分期,以非癌症组或HBV组为对照,单一和联合四种miRNAs筛查诊断早期HCC效能均不令人满意。以健康对照组为对照,单一miRNA筛查诊断早期HCC效能最好的是miR-27a,AUC为0.860,灵敏性为92.3%,特异性为73.3%;联合四种miRNAs诊断的AUC提高为0.920,灵敏性为92.3%,特异性提高为83.3%。5.经统计分析验证,构建的诊断模型和风险分析模型稳定。这四种miRNAs的相对表达量越低,患HCC风险越大。结论1.与对照组相比,本研究确定了在HCC患者血清中的miR-125b、miR-223、miR-27a、mi R-26a相对表达水平显著降低。2.四种miRNAs联合检测能够显著地提高诊断HCC和早期HCC的灵敏性、特异性和准确性。3.四种miRNAs相对表达量与非癌症人群患HCC风险呈负相关。有望用于临床,成为新的诊断早期HCC的血清标志物。
[Abstract]:Objective circulating tumor markers are helpful for the diagnosis of hepatocellular carcinoma (HCC) in the early stage. However, the HCC marker for auxiliary clinical diagnosis is not satisfactory, the main problem is its accuracy, sensitivity and specificity are low. The research direction of microRNAs (miRNAs) has brought new ideas. The possibility and clinical value of MI R-125b, miR-223, miR-27a and MI R-26a as HCC serum markers are studied to improve the accuracy, sensitivity and specificity of early HCC in screening and diagnosis by joint detection. Methods 90 cases of primary hepatitis B hepatitis B virus (hepatitis B virus, HBV) in the Cancer Hospital of Medical University Of Tianjin are selected. In the experimental group (group HCC), 30 healthy volunteers (healthy control group) and 30 patients with HBV (group HBV) were used as the control group. The early HCC patients were defined by the Barcelona staging (Barcelona Clinic Liver Cancer, BCLC) and TNM (Tumor-node-etastasis) staging system respectively. N, qRT-PCR) detected the serum miR-125b, miR-223, MI R-27a and miR-26a, and analyzed the relative expression of MI RNAs by 2- Delta Delta Ct. Using R 3.1 software to complete the statistical analysis. After the single index screening, the multiple index joint diagnosis and early childhood were implemented by the single index screening model, and applied to the health control group, the group, and non cancer. The patient's work curve (receiver operating characteristic curve, ROC) was analyzed in the +HBV group of the healthy control group, and the sensitivity and specificity of the diagnosis were determined, and the stability of the model was determined by Bootstrap. Results 1. compared with the healthy control group and the HBV group, miR-125b, miR-223, miR-27a in the serum of the HCC patients, respectively. MiR-26a relative expression level decreased (P0.0001).2. in non cancer group, and single mi RNA screening was best for miR-27a, AUC was 0.849, sensitivity was 73%, specificity was 85%, AUC increased by 0.870, sensitivity increased 79.8%, specificity was 81.7%. in healthy control group as control, single miRNA. The best screening diagnostic HCC was miR-27a, AUC was 0.930, the sensitivity was 94%, the specificity was 77%, the AUC of the combined four miRNAs diagnosis was 0.970, the sensitivity was 94%, the specificity was improved to the HBV group, and the single miRNA screening was the best for miR-223, AUC 0.826, the sensitivity 73% and the specificity 83.3%. The AUC improvement of the four miRNAs diagnoses was 0.833, the sensitivity increased 82%, the specificity was 76.7%.3. based on the BCLC staging and the non cancer group as the control. The best HCC efficacy was miR-223, AUC was 0.793, the sensitivity was 70.4%, the specificity was 81.7%, four miRNAs diagnostic AUC increased 0.843, and the sensitivity increased 81. .5%, the specificity was 75.0%. in the healthy control group. The best diagnosis of early HCC by single miRNA screening was miR-27a, AUC was 0.920, the sensitivity was 81%, and the specificity was 90%; the AUC of the combined four miRNAs diagnoses was 0.960, the sensitivity was 80%, the specificity was increased to 100.0%. in HBV group, and the single miRNA screening was used to diagnose the early HCC effect. The best is miR-223, AUC is 0.809, the sensitivity is 74.1%, the specificity is 83.3%; the AUC of the combined four miRNAs diagnosis is 0.812, the sensitivity is 70.4%, the specificity is 83.3%.4. based on the TNM staging, the non cancer group or the HBV group as the control, the single and combined four miRNAs screening diagnosis early HCC efficacy is not satisfactory. In the health control group, the control group is not satisfactory. The best diagnosis of early HCC was miR-27a, AUC was 0.860, the sensitivity was 0.860, the sensitivity was 92.3%, the specificity was 73.3%, the AUC of the combined four miRNAs diagnosis was 0.920, the sensitivity was 92.3%, the specificity was improved by 83.3%.5. by statistical analysis, and the constructed diagnostic model and the risk analysis model were stable. The relative of the four miRNAs The lower the amount of expression, the greater the risk of developing HCC. Conclusion 1. compared with the control group, the present study determined that the relative expression level of miR-125b, miR-223, miR-27a, MI R-26a in the serum of HCC patients was significantly lower than that of the.2. and four miRNAs combinations, which could significantly improve the sensitivity, specificity and accuracy of the four kinds of.3.. There is a negative correlation between the amount and the risk of HCC in non cancer patients. It is expected to be used as a new serum marker for early diagnosis of HCC.

【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R735.7

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