全基因组拷贝数变异与卵巢肿瘤异质性的关联研究

发布时间：2018-04-18 04:34

本文选题：卵巢肿瘤 + 异质性　；参考：《北京协和医学院》2017年博士论文

【摘要】：背录及目的卵巢癌目前已成为致死率最高的妇科恶性肿瘤,因其极高的恶性程度,对卵巢癌异质性的研究显得非常必要。近年来,拷贝数变异成为疾病机制探讨中的重要部分,目前已有1500多项常见CNVs与疾病的关联研究。本研究旨在探讨拷贝数变异与卵巢肿瘤的异质性可能的关联及对其预后可能造成什么影响。方法本研究为回顾性实验。收集了北京协和医院2005年～2015年见卵巢上皮性肿瘤54例病例及随访资料,其病理经一位病理科医生复审,对石蜡标本上肿瘤所在区域进行取材制作组织芯片,进行BRD4、DDB1、DNM2、FAK、MARK4、PRP19、RHEB、BCAT1免疫组织化学染色。采集数字图像,由病理科医师随机双盲阅片进行评分,将所得的评分与临床资料关联分析。临床资料主要包括卵巢癌病理类型、患者行标准TC化疗至CA125回落至正常水平的时间、无进展生存期及总生存期。数据分析方面采用IBM SPSS Statistics 19.0分析。结果1.BRD4在高级别浆乳癌与子宫内膜样癌之间的表达(p=0.021)、在高级别浆乳癌与移行细胞癌间的表达(p=0.036)具有显著性差异;DDB1在透明细胞癌与低级别浆乳癌(p=0.012)及子宫内膜样癌(p=0.015)之间的表达有显著性差异。其余蛋白的表达在各不同病理类型间没有统计学差异。2.BRD4、FAK、MARK4的表达与化疗敏感性的相关性具有显著性(p值分别为0.028、0.004、0.005)。3.MARK4、BCAT1的表达与无进展生存期的相关性有显著性(p值分别为0.002、0.003)。4.BRD4在总生存期以30个月为界限的两个分组中有显著差异(p=0.010),DDB1在总生存期以40个月及50个月为界限的分组中有显著差异(p值分别为 0.011、0.008)。5.某些位点的拷贝数变异与卵巢肿瘤的异质性是有相互关联的,但尚不能证实CNVs是否可以作为肿瘤异质性的标志物,只能为以后进一步的深入研究提供一些线索。结论1、BRD4和DDB1的表达不同病理类型间有统计学差异。由此推断,部分CNVs与卵巢肿瘤病理类型有一定的关联,但通过BRD4与DDB1的分子作用机制尚不能解释这种关联。2、BRD4、FAK、MARK4的表达与化疗敏感性相关且Pearson相关系数0,表明这些蛋白表达量越高,患者的化疗敏感性越低。3、MARK4和BCAT1与患者的无进展生存期显著相关,BRD4与DDB1与患者总生存期显著相关。其中MARK4、BCAT1和BRD4的表达都是与PFS/OS程正相关,DDB1的表达与OS呈负相关。4、通过分析上述与卵巢肿瘤异质性相关的蛋白免疫组化染色评分的Cutoff值,证实在化疗敏感性及无进展生存期两个部分是可以找到Cutoff值上下差异具有显著性的数值的,为我们以后对这些蛋白免疫组化染色的阴性及阳性判读提供了一些参考。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.31

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