胰腺癌血漿診斷標(biāo)志物譜的篩選及驗證
發(fā)布時間：2018-09-07 10:04
【摘要】：胰腺癌(pancreatic cancer, PC)是一種惡性程度很高的腫瘤,其發(fā)病率位列腫瘤發(fā)病率第十。由于早期發(fā)病缺乏明顯的癥狀,沒有較好的早期診斷工具難以早期發(fā)現(xiàn),進展期患者沒有有效的治療方式使得胰腺癌的預(yù)后很差,五年生存率低于10%。當(dāng)前胰腺癌常用的診斷標(biāo)志物CA19-9對早期患者的診斷不夠穩(wěn)定,靈敏度和特異性均不夠理想。因此,為了提高胰腺癌患者的生存期急需發(fā)現(xiàn)新的診斷標(biāo)志物。本課題的主要目的就是為胰腺癌尋找有價值的血漿診斷工具,分析鑒定其診斷靈敏度和特異性為臨床應(yīng)用奠定前期基礎(chǔ)。本課題采用407例血漿標(biāo)本(包括胰腺癌、慢性胰腺炎、正常對照、結(jié)直腸者、胃癌和肝癌),檢測了七個候選標(biāo)志物和CA19-9的表達情況。七個候選標(biāo)志物(miR-20A, miR-21, miR-25, miR-155, miR-196A, miR-210和巨噬細胞抑制因子-1(Macrophage Inhibitory Cytokine-1, MIC-1))均有報道在胰腺癌中的高表達,是可能的診斷標(biāo)志物。本實驗設(shè)計包含一個訓(xùn)練組、一個驗證組和一個獨立的雙盲實驗。訓(xùn)練組的目的是從候選標(biāo)志物中篩選特異的診斷標(biāo)志物,并利用篩選出的標(biāo)志物建立診斷標(biāo)志物譜的聯(lián)合方程。研究結(jié)果發(fā)現(xiàn)：與正常對照相比,所有候選標(biāo)志物均在胰腺癌患者的血漿中高表達(P0.001),但miR-155, miR-196A, miR-210在胰腺炎患者中亦高表達,與胰腺癌患者的表達水平無顯著性差異。只有miR-20A, miR-21, miR-25, MIC-1和CA19-9在胰腺癌中高表達且可以區(qū)別胰腺癌和其他消化道腫瘤(包括結(jié)直腸癌、胃癌和肝癌),但miR-155, miR-196A, miR-210在其他消化道腫瘤也高表達,對胰腺癌無組織特異性。因此,miR-20A, miR-21, miR-25, MIC-1和CA19-9是在胰腺癌特異性上調(diào)表達的標(biāo)志物,利用多因素logistic回歸分析我們建立2個包含多個標(biāo)志物的診斷方程用于診斷胰腺癌,他們是：Index1=1.971×ln(MIC-1)+1.795×ln(miR-21)+1.020×ln(CA19-9)-42.305;Index2=2.138×ln(MIC-1)+1.772×ln(miR-25)+1.125×ln(CA19-9)-45.006.兩個方程用于診斷胰腺癌的閾值均為0。訓(xùn)練組中,比較胰腺癌和所有非胰腺癌,Index1的曲線下面積(AUC)是0.968(95%CI,0.947-0.989), Index2的AUC是0.967(95%CI,0.945-0.989),單獨CA19-9的AUC是0.895(95%CI,0.838-0.952)。Index1、Index2和CA19-9的靈敏度分別是0.895、0.895、0.816,特異度分別是0.909、0.915、0.933,準(zhǔn)確度分別是0.904、0.908、0.892。可見多個標(biāo)志物的聯(lián)合應(yīng)用能提高單一標(biāo)志物的診斷靈敏度和準(zhǔn)確度。驗證組用于鑒定所選擇建立的聯(lián)合方程的診斷價值。驗證組中,Index1的AUC是0.933(95%CI：0.874-0.992),而Index2的AUC是0.921 (95%CI:0.856-0.986),CA19-9的AUC是0.793(95%CI,0.687-0.899)。Index1、Index2和CA19-9的靈敏度分別是0.892、0.838、0.649,特異度分別是0.913、0.925、0.913。從訓(xùn)練組和驗證組的結(jié)果可見,兩個聯(lián)合方程的診斷靈敏度和準(zhǔn)確度比單一標(biāo)志物CA19-9好。雙盲實驗用于分析所篩選出的聯(lián)合方程的臨床應(yīng)用可行性。在雙盲實驗中,兩個聯(lián)合方程與CA19-9的診斷靈敏度和特異度相同。相關(guān)性分析發(fā)現(xiàn)多數(shù)標(biāo)志物的表達水平與患者的臨床指標(biāo)如性別、年齡、高血壓史、糖尿病史等均無相關(guān)性。Index1和Index2的表達水平與性別和糖尿病史有一定相關(guān)性,但相關(guān)系數(shù)很小。隨訪了100例胰腺癌患者的生存狀態(tài)并分析候選標(biāo)志物表達與胰腺癌預(yù)后之間的相關(guān)性。結(jié)果發(fā)現(xiàn),6個miRNA、MIC-1、CA19-9和兩個聯(lián)合方程的表達水平與胰腺癌患者的預(yù)后均無相關(guān)性。本課題的創(chuàng)新點為：采用多種標(biāo)志物構(gòu)建聯(lián)合方程診斷胰腺癌；分析了候選標(biāo)志物和聯(lián)合方程的組織特異性；設(shè)計上除了訓(xùn)練組、驗證組外還有雙盲實驗組,系統(tǒng)地篩選驗證獲得診斷聯(lián)合方程。綜上所述,本課題鑒定出兩個診斷靈敏度和特異性較好的胰腺癌特異診斷聯(lián)合方程。為實現(xiàn)其臨床應(yīng)用,還需要深入研究其作為診斷標(biāo)志物的價值和潛能。
[Abstract]:Pancreatic cancer (PC) is a highly malignant tumor with the tenth highest incidence. Because of the lack of obvious symptoms in the early stage, it is difficult to detect early without good early diagnostic tools. The current diagnostic marker of pancreatic cancer, CA19-9, is not stable, sensitive and specific enough for early diagnosis. Therefore, in order to improve the survival time of pancreatic cancer patients, it is urgent to find new diagnostic markers. In this study, 407 plasma specimens (including pancreatic cancer, chronic pancreatitis, normal control, colorectal cancer, gastric cancer and liver cancer) were used to detect the expression of seven candidate markers and CA19-9. Seven candidate markers (Mi-20A, Mi-21, Mi-25, Mi-155, Mi-196A, Mi-210 and Giant) Macrophage Inhibitory Cytokine-1 (MIC-1) has been reported to be highly expressed in pancreatic cancer and is a potential diagnostic marker. This study included a training group, a validation group and an independent double-blind trial. The aim of the training group was to screen specific diagnostic markers from candidate markers and utilize them. The results showed that all the candidate markers were highly expressed in plasma of pancreatic cancer patients (P 0.001), but the expressions of microRNAs-155, microRNAs-196A and microRNAs-210 were also high in pancreatitis patients. There was no significant difference in the expression level between pancreatic cancer patients and pancreatic cancer patients. R-20A, Mi-21, Mi-25, MIC-1 and CA19-9 are highly expressed in pancreatic cancer and differentiate pancreatic cancer from other gastrointestinal cancers (including colorectal cancer, gastric cancer and liver cancer), but Mi-155, Mi-196A, and Mi-210 are also highly expressed in other gastrointestinal cancers and are not tissue-specific for pancreatic cancer. Using multivariate logistic regression analysis, we established two diagnostic equations containing multiple markers for the diagnosis of pancreatic cancer: Index1 = 1.971 *ln (MIC-1) + 1.795 *ln (Mi-21) + 1.020 *ln (CA19-9) - 42.305; Index2 = 2.138 *ln (MIC-1) + 1.772 *ln (Mi-25) + 1.125 *ln (CA19-9) - 45.006. In the training group, the AUC of Index1 was 0.968 (95% CI, 0.947-0.989), the AUC of Index2 was 0.967 (95% CI, 0.945-0.989), and the AUC of CA19-9 was 0.895 (95% CI, 0.838-0.952). Index1, Index2, and CA19-9 were 0.895 (0.895, 0.895, 0.895, 0.8, 0.989) respectively. 16, specificity 0.909, 0.915, 0.933, accuracy 0.904, 0.908, 0.892, respectively. It can be seen that the combination of multiple markers can improve the diagnostic sensitivity and accuracy of a single marker. The ACU of CA19-9 was 0.793 (95% CI, 0.687-0.899). The sensitivity of Index1, Index2 and CA19-9 were 0.892, 0.838, 0.649, and the specificity was 0.913, 0.925, 0.913, respectively. The results of the training group and the verification group showed that the diagnostic sensitivity and accuracy of the two combined equations were better than that of the single marker CA19-9. In the double-blind experiment, the sensitivity and specificity of the two equations were the same as that of CA19-9. Correlation analysis showed that the expression levels of most of the markers were not correlated with clinical parameters such as sex, age, history of hypertension and diabetes mellitus. The survival status of 100 patients with pancreatic cancer was followed up and the correlation between the expression of candidate markers and the prognosis of pancreatic cancer was analyzed. The innovations of this study are as follows: using multiple markers to construct the joint equation for the diagnosis of pancreatic cancer; analyzing the tissue specificity of candidate markers and joint equation; designing a double-blind experimental group besides training group and validation group, and systematically screening and validating to obtain the joint equation of diagnosis. In order to realize its clinical application, it is necessary to study its value and potential as a diagnostic marker.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.9
本文編號：2227941
[Abstract]:Pancreatic cancer (PC) is a highly malignant tumor with the tenth highest incidence. Because of the lack of obvious symptoms in the early stage, it is difficult to detect early without good early diagnostic tools. The current diagnostic marker of pancreatic cancer, CA19-9, is not stable, sensitive and specific enough for early diagnosis. Therefore, in order to improve the survival time of pancreatic cancer patients, it is urgent to find new diagnostic markers. In this study, 407 plasma specimens (including pancreatic cancer, chronic pancreatitis, normal control, colorectal cancer, gastric cancer and liver cancer) were used to detect the expression of seven candidate markers and CA19-9. Seven candidate markers (Mi-20A, Mi-21, Mi-25, Mi-155, Mi-196A, Mi-210 and Giant) Macrophage Inhibitory Cytokine-1 (MIC-1) has been reported to be highly expressed in pancreatic cancer and is a potential diagnostic marker. This study included a training group, a validation group and an independent double-blind trial. The aim of the training group was to screen specific diagnostic markers from candidate markers and utilize them. The results showed that all the candidate markers were highly expressed in plasma of pancreatic cancer patients (P 0.001), but the expressions of microRNAs-155, microRNAs-196A and microRNAs-210 were also high in pancreatitis patients. There was no significant difference in the expression level between pancreatic cancer patients and pancreatic cancer patients. R-20A, Mi-21, Mi-25, MIC-1 and CA19-9 are highly expressed in pancreatic cancer and differentiate pancreatic cancer from other gastrointestinal cancers (including colorectal cancer, gastric cancer and liver cancer), but Mi-155, Mi-196A, and Mi-210 are also highly expressed in other gastrointestinal cancers and are not tissue-specific for pancreatic cancer. Using multivariate logistic regression analysis, we established two diagnostic equations containing multiple markers for the diagnosis of pancreatic cancer: Index1 = 1.971 *ln (MIC-1) + 1.795 *ln (Mi-21) + 1.020 *ln (CA19-9) - 42.305; Index2 = 2.138 *ln (MIC-1) + 1.772 *ln (Mi-25) + 1.125 *ln (CA19-9) - 45.006. In the training group, the AUC of Index1 was 0.968 (95% CI, 0.947-0.989), the AUC of Index2 was 0.967 (95% CI, 0.945-0.989), and the AUC of CA19-9 was 0.895 (95% CI, 0.838-0.952). Index1, Index2, and CA19-9 were 0.895 (0.895, 0.895, 0.895, 0.8, 0.989) respectively. 16, specificity 0.909, 0.915, 0.933, accuracy 0.904, 0.908, 0.892, respectively. It can be seen that the combination of multiple markers can improve the diagnostic sensitivity and accuracy of a single marker. The ACU of CA19-9 was 0.793 (95% CI, 0.687-0.899). The sensitivity of Index1, Index2 and CA19-9 were 0.892, 0.838, 0.649, and the specificity was 0.913, 0.925, 0.913, respectively. The results of the training group and the verification group showed that the diagnostic sensitivity and accuracy of the two combined equations were better than that of the single marker CA19-9. In the double-blind experiment, the sensitivity and specificity of the two equations were the same as that of CA19-9. Correlation analysis showed that the expression levels of most of the markers were not correlated with clinical parameters such as sex, age, history of hypertension and diabetes mellitus. The survival status of 100 patients with pancreatic cancer was followed up and the correlation between the expression of candidate markers and the prognosis of pancreatic cancer was analyzed. The innovations of this study are as follows: using multiple markers to construct the joint equation for the diagnosis of pancreatic cancer; analyzing the tissue specificity of candidate markers and joint equation; designing a double-blind experimental group besides training group and validation group, and systematically screening and validating to obtain the joint equation of diagnosis. In order to realize its clinical application, it is necessary to study its value and potential as a diagnostic marker.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.9
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