本文選題：卵巢腫瘤 + 異質(zhì)性�。� 參考：《北京協(xié)和醫(yī)學院》2017年博士論文

【摘要】：背錄及目的卵巢癌目前已成為致死率最高的婦科惡性腫瘤,因其極高的惡性程度,對卵巢癌異質(zhì)性的研究顯得非常必要。近年來,拷貝數(shù)變異成為疾病機制探討中的重要部分,目前已有1500多項常見CNVs與疾病的關(guān)聯(lián)研究。本研究旨在探討拷貝數(shù)變異與卵巢腫瘤的異質(zhì)性可能的關(guān)聯(lián)及對其預后可能造成什么影響。方法本研究為回顧性實驗。收集了北京協(xié)和醫(yī)院2005年～2015年見卵巢上皮性腫瘤54例病例及隨訪資料,其病理經(jīng)一位病理科醫(yī)生復審,對石蠟標本上腫瘤所在區(qū)域進行取材制作組織芯片,進行BRD4、DDB1、DNM2、FAK、MARK4、PRP19、RHEB、BCAT1免疫組織化學染色。采集數(shù)字圖像,由病理科醫(yī)師隨機雙盲閱片進行評分,將所得的評分與臨床資料關(guān)聯(lián)分析。臨床資料主要包括卵巢癌病理類型、患者行標準TC化療至CA125回落至正常水平的時間、無進展生存期及總生存期。數(shù)據(jù)分析方面采用IBM SPSS Statistics 19.0分析。結(jié)果1.BRD4在高級別漿乳癌與子宮內(nèi)膜樣癌之間的表達(p=0.021)、在高級別漿乳癌與移行細胞癌間的表達(p=0.036)具有顯著性差異;DDB1在透明細胞癌與低級別漿乳癌(p=0.012)及子宮內(nèi)膜樣癌(p=0.015)之間的表達有顯著性差異。其余蛋白的表達在各不同病理類型間沒有統(tǒng)計學差異。2.BRD4、FAK、MARK4的表達與化療敏感性的相關(guān)性具有顯著性(p值分別為0.028、0.004、0.005)。3.MARK4、BCAT1的表達與無進展生存期的相關(guān)性有顯著性(p值分別為0.002、0.003)。4.BRD4在總生存期以30個月為界限的兩個分組中有顯著差異(p=0.010),DDB1在總生存期以40個月及50個月為界限的分組中有顯著差異(p值分別為 0.011、0.008)。5.某些位點的拷貝數(shù)變異與卵巢腫瘤的異質(zhì)性是有相互關(guān)聯(lián)的,但尚不能證實CNVs是否可以作為腫瘤異質(zhì)性的標志物,只能為以后進一步的深入研究提供一些線索。結(jié)論1、BRD4和DDB1的表達不同病理類型間有統(tǒng)計學差異。由此推斷,部分CNVs與卵巢腫瘤病理類型有一定的關(guān)聯(lián),但通過BRD4與DDB1的分子作用機制尚不能解釋這種關(guān)聯(lián)。2、BRD4、FAK、MARK4的表達與化療敏感性相關(guān)且Pearson相關(guān)系數(shù)0,表明這些蛋白表達量越高,患者的化療敏感性越低。3、MARK4和BCAT1與患者的無進展生存期顯著相關(guān),BRD4與DDB1與患者總生存期顯著相關(guān)。其中MARK4、BCAT1和BRD4的表達都是與PFS/OS程正相關(guān),DDB1的表達與OS呈負相關(guān)。4、通過分析上述與卵巢腫瘤異質(zhì)性相關(guān)的蛋白免疫組化染色評分的Cutoff值,證實在化療敏感性及無進展生存期兩個部分是可以找到Cutoff值上下差異具有顯著性的數(shù)值的,為我們以后對這些蛋白免疫組化染色的陰性及陽性判讀提供了一些參考。
[Abstract]:Ovarian cancer has become the most fatal gynecologic malignant tumor. Because of its high degree of malignancy, it is necessary to study the heterogeneity of ovarian cancer.In recent years, copy number variation has become an important part of the study of disease mechanism. At present, there are more than 1500 studies on the association between CNVs and disease.The aim of this study was to investigate the possible association between copy number variation and heterogeneity of ovarian tumors and its possible impact on prognosis.Methods this study is a retrospective experiment.54 cases of ovarian epithelial tumor were collected from 2005 to 2015 in Peking Union Hospital. The pathological data of 54 cases were reviewed by a pathologist, and tissue microarray was made from the region where the tumor was located on the paraffin wax specimen.BRD4 DDB1 DNM2 + MARK4 + PRP19 RHEBX BCAT1 immunohistochemical staining was performed.Digital images were collected and graded by random double-blind radiographs of pathologists. The scores were correlated with clinical data.The clinical data mainly included pathological types of ovarian cancer, the time between standard TC chemotherapy and CA125 returning to normal level, progression free survival and total survival.IBM SPSS Statistics 19.0 was used to analyze the data.Results there was a significant difference in the expression of 1.BRD4 between high grade plasma breast carcinoma and endometrial carcinoma, and between high grade plasma breast cancer and transitional cell carcinoma.There was a significant difference in the expression between the two groups.There was no significant difference in the expression of other proteins among different pathological types. 2. The correlation between the expression of BRD4, FAK4, MARK4 and chemosensitivity was significant (p = 0.028, 0.004, 0.005, respectively. 3. The expression of BCAT1 of MARK4 was significantly correlated with the survival time without progression, respectively.There was significant difference between two groups with a total survival limit of 30 months (P < 0.010) and a significant difference between two groups with a total survival time of 40 months and 50 months (P < 0.05).The copy number variation of some loci is related to the heterogeneity of ovarian tumors, but it can not be confirmed whether CNVs can be used as a marker of tumor heterogeneity, which can only provide some clues for further research.Conclusion 1 the expression of BRD 4 and DDB1 were significantly different in different pathological types.It is inferred that some of CNVs is related to the pathological types of ovarian tumors, but the molecular mechanism of BRD4 and DDB1 can not explain the correlation between the expression of BRD4FAKMARK4 and chemosensitivity, and the correlation coefficient of Pearson is 0, which indicates that the higher the expression of these proteins, the higher the expression of these proteins.The lower the chemosensitivity of patients, the lower the sensitivity. 3MARK4 and BCAT1 were significantly correlated with progressive survival. BRD4 and DDB1 were significantly correlated with total survival.The expression of MARK4 BCAT1 and BRD4 was negatively correlated with the expression of PFS/OS, and the expression of DDB1 was negatively correlated with OS. The Cutoff value of the immunohistochemical staining score of the above proteins related to the heterogeneity of ovarian tumors was analyzed.It was proved that there were significant differences in Cutoff values between the two parts of chemosensitivity and progression-free survival, which provided some references for the negative and positive interpretation of these proteins by immunohistochemical staining.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R737.31

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