1、miR-498、miR-let-7d及miR-let-7e与乳腺癌相关性的研究 2、乳腺叶状肿瘤的临床特点及预后分析

发布时间：2018-03-15 10:25

本文选题：乳腺叶状肿瘤　切入点：良性　出处：《北京协和医学院》2015年博士论文　论文类型：学位论文

【摘要】：目的：初步探讨乳腺叶状肿瘤三种组织学类型间临床特征方面的差异及影响叶状肿瘤无病生存情况的因素。研究方法：回顾性分析我院2002年1月至2012年12月间收治的共246例女性乳腺叶状肿瘤患者的相关临床资料,包括患者发病年龄、就诊年龄、病程、初治肿瘤大小、肿瘤部位、病理类型、有无溃疡、初治手术时间及方式、有无局部复发或远处转移、有无纤维腺瘤病史、复发期间有无病理改变、局部复发次数及术后治疗。并进行随访至2014-5-20日。中位随访时间为48个月,56例出现局部复发,5例出现远处转移,1例局部复发伴远处转移。65人失访,失访率为26%。结果：乳腺叶状肿瘤三种组织学类型间单因素分析,发现发病年龄,就诊年龄,初治肿瘤大小,有无溃疡,初治手术方式及有无远处转移P值均0.05(P=0.014,P=0.018,P0.000, P=0.003, P0.000, P=0.001),即三种组织学类型的叶状肿瘤在上述方面存在差异,且差异有统计学意义。而无病生存时间及有无复发P值分别为0.055及0.060,接近0.05,趋向于有统计学差异。多因素分析采用有序多分类Logistic回归,模型中有无远处转移及局部肿物切除P值分别为0.041及0.018,均0.05,表现为有统计学差异。而初治肿瘤大小P值为0.052,趋向于有统计学差异。在研究乳腺叶状肿瘤无病生存的预测因素时,Kaplan-Meier单因素分析发现,有无纤维腺瘤病史为预测叶状肿瘤复发的危险因素,P值0.000.而局部肿物切除术比乳腺单纯切除及改良根治术有着更高的局部复发率,P值为0.043。且三种病理类型叶状肿瘤的复发风险,恶性交界性良性,且P值为0.083,趋向于有统计学意义。Cox多因素模型中,手术方式、有无纤维腺瘤病史及病理类型均有统计学意义,P值分别为0.009、0.001及0.000。结论：良性、交界性及恶性乳腺叶状肿瘤间在有无远处转移、初治手术方式及初治肿瘤大小方面存在差异,即肿瘤恶性程度越高,肿瘤越大,越容易出现远处转移。手术方式、有无纤维腺瘤病史及病理类型是影响乳腺叶状肿瘤无病生存的独立预后因素。目的：本研究的目的是分析miR-498、miR-let-7d5p、miR-let-7d3p、miR-let-7e5p及miR-let-7e3p在乳腺浸润性导管癌中的表达及其与临床病理特征的关系。方法：前期研究中,我们利用Snail诱导永生化的乳腺癌细胞系MCF-10A发生EMT,然后利用miRNA芯片分析发生EMT前后MCF-10A中miRNA的表达情况,发现miR-498在EMT后表达量明显升高,说明这个miRNA可能对EMT有促进作用。另外,我们构建了一个含有1000多种microRNAs前体的病毒库,然后用该病毒库去感染非转移性乳腺癌细胞系MCF-7,通过Transwell侵袭实验去选择并富集这些透膜细胞,并形成单克隆。最后,对这些单克隆进行microRNAs测序,发现了一些对细胞侵袭转移可能具有促进作用的microRNAs,其中包括miR-let-7d及miR-let-7e。然后,利用RT-PCR技术,检测miR-49、 miR-let-7d5p、 miR-let-7d3p、 miR-let-7e5p及miR-let-7e3p在正常乳腺组织及乳腺癌组织中的表达,并同时收集这些乳腺癌患者的临床病理资料。结果：相比乳腺正常组织,miR-498、miR-let-7d3p及miR-let-7e3p在乳腺癌中的表达下调,且差异有统计学意义(P=0.0004,0.0012及0.0453)。miR-let-7d3p在乳腺癌组织中的表达与患者月经初潮年龄、P53及脉管瘤栓呈相关性(P=0.0177,0.0044及0.0166)。miR-let-7e5p在乳腺癌组织中的表达与ER、PR、EGFR及分子分型有相关性(P=0.0091,0.0096,0.0166及0.0287),但与Her-2表达及Ki-67指数无关(P=0.6733,P=0.8121),与CK56有相关趋势(P=0.0550)。miR-let-7e3p在乳腺癌组织中的表达与脉管瘤栓呈相关性(P=0.0398)。结论：miR-498、miR-let-7d3p及miR-let-7e3p在乳腺浸润性导管癌中可能具有抑癌作用。miR-let-7d3p在月经初潮晚、无脉管瘤栓及P53阳性的乳腺癌患者中表达量高,其与P53的具体相互作用机制不详,但前者提示,miR-let-7d3p在乳腺癌中是一种保护性因素。miR-let-7e5p在ER(+)、PR (+)、CK56 (-)、EGFR (-)及Luminal型乳腺癌中高表达,提示miR-let-7e5p在乳腺癌中是一种保护性因素,且miR-let-7e5p与ER、PR、CK56及EGFR间的相互联系及作用机制,有待于进一步研究。miR-let-7e3p与脉管瘤栓成负相关,提示miR-let-7e3p在乳腺癌中可能具有抑制转移的作用。
[Abstract]:Objective: To investigate the difference factors of phyllodes tumor of the breast three histological types between the clinical characteristics and influence of phyllodes tumor disease free survival. Methods: retrospective analysis of our hospital from January 2002 to December 2012 were a total of 246 cases of female patients with breast phyllodes tumor related clinical data, including age, age of patients. The course of treatment, tumor size, tumor location, pathological type, ulceration, initial treatment and operation time, there is no local recurrence or distant metastasis, there is no recurrence during the history of fibroadenoma, without pathological changes, the number of local recurrence and postoperative treatment. And follow-up to 2014-5-20 days. The median follow-up time 48 months, 56 cases had local recurrence and metastasis occurred in 5 cases, 1 cases of local recurrence and distant metastasis.65 people lost, the lost rate was 26%. results: three breast phyllodes tumor histological types The single factor analysis found that the age of onset, age, initial treatment of ulceration, tumor size, initial treatment of surgery and metastasis P values were 0.05 (P=0.014, P=0.018, P0.000, P=0.003, P0.000, P=0.001), namely the three histological types of phyllodes tumor differences in the above aspects, there were and the difference of disease-free survival and recurrence P values were 0.055 and 0.060, close to 0.05, tend to have significant differences. Multivariate analysis using Logistic regression model, there is no distant metastasis and local tumor resection P values were 0.041 and 0.018, 0.05, performance there were significant differences in tumor size and initial treatment. The P value is 0.052, tend to have significant differences. No predictors of survival in the study of breast phyllodes tumors, Kaplan-Meier single factor analysis found that there is no history for the prediction of fibroadenoma of phyllodes tumor recurrence The risk factors of P value, 0.000. and local tumor resection than mastectomy and modified radical mastectomy with higher rates of local recurrence, P value of the risk of recurrence of 0.043. and three kinds of pathological types of malignant phyllodes tumor, borderline and benign, P value is 0.083, tend to have statistical significance in multivariate.Cox model there is no way, surgery, history of fibroadenoma and pathological types were statistically significant, P = 0.009,0.001 and 0.000. conclusion: benign, borderline and malignant phyllodes tumors of the breast in metastasis, initial treatment of surgery and early treatment of tumor size differences, namely the higher degree of malignancy, tumor size and more prone to distant metastasis. There is no history of surgery, fibroadenoma and pathological types were independent prognostic factors of breast phyllodes tumor free survival. Objective: the purpose of this study is to analyze miR-498, miR-let-7d5p, M IR-let-7d3p, miR-let-7e5p and miR-let-7e3p in breast invasive ductal carcinoma and its relationship with clinical pathological features. Methods: Based on the previous research, we use Snail induced breast cancer cell lines immortalized MCF-10A EMT, and then use the miRNA chip analysis of expression of MCF-10A in miRNA before and after EMT, miR-498 expression in EMT the amount was increased, the miRNA may contribute to EMT. In addition, we constructed a microRNAs precursor containing more than 1000 kinds of virus database, and then use the virus to infect non metastatic breast cancer cell line MCF-7 by Transwell invasion assay to select and enrichment of these cell membrane permeability, and the formation of monoclonal. Finally, microRNAs sequencing was performed on these monoclonal, discovered may promote the invasion and metastasis of microRNAs cells, including miR-let-7d and miR-let-7 E. then, using the technology of RT-PCR, miR-let-7d5p, miR-let-7d3p, miR-49 detection, the expression of miR-let-7e5p and miR-let-7e3p in normal breast tissue and breast cancer tissues, and also collected clinical data of these patients with breast cancer. Results: compared with normal breast tissue, miR-498, expression of miR-let-7d3p and miR-let-7e3p in breast cancer, was statistically significant and the difference (P=0.0004,0.0012 and 0.0453).MiR-let-7d3p expression in breast carcinoma patients with age at menarche and menstruation, P53 and vascular tumor thrombus (P=0.0177,0.0044 and 0.0166) were correlated with the expression of ER,.MiR-let-7e5p in breast cancer PR, EGFR and molecular typing correlation (P=0.0091,0.0096,0.0166 and 0.0287), but not with the expression of Her-2 and the Ki-67 index (P=0.6733, P=0.8121), a trend with CK56 (P=0.0550).MiR-let-7e3p expression in breast cancer tissue and vascular tumor Bolt is correlation (P=0.0398). Conclusion: miR-498, miR-let-7d3p and miR-let-7e3p in invasive breast may have a tumor suppressor role of.MiR-let-7d3p in the late menarche ductal carcinoma, no expression of tumor thrombus and P53 positive breast cancer patients was high, and P53 specific interaction mechanism is unknown, but the former suggested that miR-let-7d3p is a protective factor of.MiR-let-7e5p in ER in breast cancer (+), PR (+), CK56 (-), EGFR (-) high expression and Luminal type of breast cancer, suggesting that miR-let-7e5p is a protective factor in breast cancer, and miR-let-7e5p and ER, PR, mutual relation and effect the mechanism of CK56 and EGFR, need to be further studied.MiR-let-7e3p negatively correlated with vascular invasion, suggesting miR-let-7e3p could inhibit metastasis in breast cancer.

【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】：2015
【分类号】：R737.9

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