膀胱癌血清lncRNA诊断模型的建立及其对膀胱癌复发监测的临床意义

发布时间：2018-03-10 05:05

本文选题：膀胱癌　切入点：lncRNAs　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:越来越多的证据表明lncRNAs在肿瘤的发生发展中起着非常重要的作用。通过检测lncRNAs在膀胱癌组织及血清中的表达水平,确定表达差异有统计学意义的lncRNAs,建立膀胱癌血清lncRNAs诊断模型。并进一步评价该模型对膀胱癌的诊断价值及与膀胱癌复发的关系。方法:1.通过检索文献获得与膀胱癌相关的差异表达的lncRNAs作为候选lncRNAs。2.通过实时荧光定量PCR(qRT-PCR)检测候选lncRNAs在80例膀胱癌组织及相对应的癌旁正常组织中的表达水平,经数据分析筛选出在膀胱癌组织和癌旁正常组织中差异表达的lncRNAs并进一步确证。3.在training阶段,上述初步筛选出的lncRNAs继续在52例健康对照者、68例良性对照者及120例膀胱癌患者的血清中通过qRT-PCR进行检测。筛选出在膀胱癌组和健康对照组以及膀胱癌组和良性对照组之间均呈差异表达的lncRNAs。将差异表达有统计学意义的lncRNAs代入logistic多元回归方程,建立膀胱癌血清lncRNA诊断模型用以区分膀胱癌组和对照组。同时用Pearson相关分析分析差异表达的lncRNAs在膀胱癌组织和相对应的血清标本中表达量的相关性。4.在validation阶段,差异表达的lncRNAs在另外48例健康对照者、52例良性对照者以及100例膀胱癌患者血清中进一步验证,并评估膀胱癌血清中建立的lncRNA诊断模型对膀胱癌的诊断效能。同时获取这100名对照者和100名膀胱癌患者的尿液标本,进行尿液脱落细胞学检查并与诊断模型的诊断效能进行对比。5.跟踪随访validation阶段100名膀胱癌患者包括61名非肌层浸润性膀胱癌患者和39名肌层浸润性膀胱癌患者,分析差异表达的lncRNAs与膀胱癌复发的关系。通过Kaplan-Meier软件和Cox比例风险回归模型分别对浸润性膀胱癌和非浸润性膀胱癌患者进行生存曲线分析和监测复发的独立预后因素的分析。结果:1.在13个候选lncRNAs分子中有11个lncRNAs分子在膀胱癌组织和癌旁组织之间呈现差异表达(p0.01)。2.在training阶段,3个lncRNAs分子在膀胱癌和健康对照组及膀胱癌和良性对照组之间均呈现差异表达。MEG3表达量下降,MALAT1和SNHG16表达量升高(均p0.01)。MEG3、SNHG16和MALAT1的受试者工作曲线下面积(AUC)分别为 0.798、0.687 和 0.640。由 MEG3、SNHG16 和 MALAT1 组成的血清 lncRNA膀胱癌诊断模型的AUC为0.865(95%CI=0.815-0.905;灵敏度为71.7%,特异度为85.8%)。同时Pearson相关分析显示MEG3、SNHG16和MALAT1在膀胱组织及相对应的血清中的表达量呈较好的相关性,MEG3(r = 0.629,p ＜ 0.05),SNHG16(r = 0.556,尸0.05)和 MALAT1(r = 0.401,p0.05)。3.在validation阶段,MEG3、SNHG16和MALAT1在膀胱癌和健康对照组及膀胱癌和良性对照组之间同样呈现差异表达(均p0.01)。膀腕癌血清lncRNA诊断模型的AUC=0.828(95%CI= 0.768-0.877;灵敏度=82.0%,特异度=73.0%)。该模型对Ta、T1和T2-T4期膀胱癌的诊断效能分别为0.778、0.805和0.880,高于尿液脱落细胞学相对应的0.548、0.604和0.682(p0.01)。4.经Kaplan-Meier分析发现,MG3表达水平低的非肌层浸润性膀胱癌患者的无复发生存率显著低于MEG3表达水平高的非肌层浸润性膀胱癌患者(p=0.028)。经Cox比例风险回归分析发现,MEG3(p = 0.046)和临床病理分期(T)(p = 0.041)是非浸润性膀胱癌患者监测复发的独立预测指标。在肌层浸润性膀胱癌组未发现与膀胱癌患者复发有关的独立预后指标。结论:1.血清MEG3、SNHG16和MALAT1具有较高的膀胱癌诊断价值。2.血清lncRNA膀胱癌诊断模型可以辅助膀胱癌诊断特别是对于早期膀胱癌的诊断具有重要意义。3.血清中的MEG3可以作为非肌层浸润性膀胱癌患者的复发监测的独立预后指标。
[Abstract]:Objective: there is growing evidence that lncRNAs in tumor development plays a very important role. Through the detection of lncRNAs in bladder cancer tissues and the expression levels of serum, determine the expression difference was statistically significant lncRNAs, the establishment of serum lncRNAs in the diagnosis of bladder cancer and to further evaluate the value model. The model for bladder cancer diagnosis and the relationship with the recurrence of bladder cancer. Methods: 1. through literature retrieval obtained differences associated with bladder cancer the expression of lncRNAs as a candidate of lncRNAs.2. by real-time fluorescence quantitative PCR (qRT-PCR) to detect the expression level of candidate lncRNAs in cancer and the corresponding 80 cases of bladder cancer tissue and adjacent normal tissues, the data analysis showed that in the bladder cancer tissues and normal tissues in the differential expression of lncRNAs and.3. was further confirmed at the training stage, the preliminary selection of lncRNAs in 52 cases of healthy controls , were measured by qRT-PCR in serum of 68 cases of benign controls and 120 cases of bladder cancer patients. Screened in bladder cancer group and healthy control group and between bladder cancer group and benign control group showed the expression of lncRNAs. in the differential expression was statistically significant lncRNAs by logistic multiple regression equation was used to distinguish between bladder cancer group and control group to establish bladder cancer model. The diagnosis of serum lncRNA expression of.4. in validation stage lncRNAs correlation and Pearson correlation analysis of differential expression analysis in bladder cancer tissues and corresponding serum samples, the differential expression of lncRNAs in 48 healthy subjects, 52 patients with benign controls and 100 cases of bladder cancer in the serum of patients with further verification, and to evaluate the diagnostic efficacy of lncRNA diagnosis model of bladder cancer in serum of bladder cancer. At the same time get the 100 control subjects and 100 patients of bladder Cancer patients urine samples, urine cytology and diagnostic efficiency and diagnosis model compared to.5. followed validation stage 100 patients with bladder cancer including 61 non muscle invasive bladder cancer and 39 patients with muscle invasive bladder cancer patients, the relationship between lncRNAs and recurrence of bladder cancer differentially expressed. Through the analysis of Kaplan-Meier software and Cox proportional hazards regression model of invasive bladder cancer and non independent prognostic factors of invasive bladder cancer patients were survival curve analysis and monitoring of recurrence. Results: 1. in 13 candidate lncRNAs molecules between 11 molecules of lncRNAs in bladder cancer tissue and paracancerous tissue showed differential expression (P0.01).2. in training phase, 3 lncRNAs molecules decreased in bladder cancer and healthy controls showed the difference between bladder cancer and benign group and control group the expression of.MEG3, MALA The T1 and SNHG16 level (P0.01).MEG3, SNHG16 and MALAT1 receiver operating curve area under the curve (AUC) were 0.798,0.687 and 0.640. by MEG3 model, the diagnosis of bladder cancer serum lncRNA SNHG16 and MALAT1 AUC composed of 0.865 (95%CI=0.815-0.905; the sensitivity was 71.7%, specificity was 85.8% and Pearson). Correlation analysis showed that MEG3, there was a good correlation between the expression of SNHG16 and MALAT1 in serum and the corresponding bladder tissues, MEG3 (r = 0.629, P < 0.05), SNHG16 (r = 0.556, P 0.05) and MALAT1 (r = 0.401, P0.05) in.3. validation MEG3, SNHG16 and MALAT1 stage. In bladder cancer and healthy control group and between bladder cancer and benign control group also showed differential expression (P0.01). Serum lncRNA in the diagnosis of bladder cancer model of wrist AUC=0.828 (95%CI= 0.768-0.877 =82.0% =73.0%; sensitivity, specificity). The model of Ta, T1 and T2-T4 in bladder cancer The diagnostic efficiency of 0.778,0.805 and 0.880 respectively, higher than the corresponding urine cytology and 0.682 0.548,0.604 (P0.01).4. by Kaplan-Meier analysis, MG3 expression level is low in non muscle invasive bladder cancer were recurrence free survival rate was significantly lower than that of MEG3 expressed high levels of non muscle invasive bladder cancer patients (p=0.028) the Cox regression analysis found that MEG3 (P = 0.046) and clinical staging (T) (P = 0.041) were independent predictors of non invasive bladder cancer recurrence. Patients with invasive bladder cancer group in the muscle layer independent prognostic indicators related to recurrence of bladder cancer patients were found. Conclusion: 1. serum MEG3, serum lncRNA can model diagnosis bladder cancer bladder cancer diagnosis value of.2. SNHG16 and MALAT1 has high diagnosis of bladder cancer particularly important.3. serum MEG3 for early diagnosis of bladder cancer An independent prognostic indicator for patients with non muscular invasive bladder cancer.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.14

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