子宫内膜异位症恶变而来的卵巢透明细胞癌miRNA表达谱及预后研究

发布时间：2018-04-28 11:09

本文选题：MiRNA + 子宫内膜异位症恶变　；参考：《北京协和医学院》2017年博士论文

【摘要】：第一部分子宫内膜异位症恶变而来的卵巢透明细胞癌miRNA表达谱研究目的:本研究通过miRNA微阵列基因芯片技术(microarray)对子宫内膜异位症(以下简称为内异症)恶变为卵巢透明细胞癌(ovarian clear cell carcinoma,OCCC)过程中各级病变,包括在位内膜、卵巢内异症、不典型内异症、癌,以及对照组的miRNA表达谱进行比较,并与并进行生物信息学分析,筛选出具有差异的miRNA及其可能靶基因。旨在寻找提示内异症恶变的生物标志,并为进一步研究内异症恶变基因通路和靶向治疗提供依据。方法:运用microarray芯片技术,对4例内异症恶变的卵巢透明细胞癌病例及其对照组石蜡切片进行miRNA表达谱研究,筛选出差异表达miRNA。对差异表达miRNA进行基因功能的富集分析(GO-enrichment Analysis),Pathway的富集分析(Pathway-enrichment Analysis),miRNA 与基因的调控网络(miRNA-Gene-Network),miRNA与pathway的调控网络(miRNA-pathway-Network)等生物信息学分析,筛选出候选miRNA。在6例验证组病理石蜡切片中采用实时荧光定量PCR(RT-PCR)验证基于芯片筛查的差异miRNA,以验证芯片表达谱的可靠性。结果:内异症恶变的OCCC的在位内膜、内异症、不典型内异症和癌四级病变对比,miR-199b-5p从在位内膜到癌一直下降,且不典型内异症到癌有显著下降;miR-200a-3p和miR-200b-3p的表达呈双向型的改变,以在位内膜为对照,在内异症和不典型内异症中下降,在癌组织中上升。内异症恶变的OCCC、符合内异症相关的卵巢癌但非内异症恶变的OCCC和与内异症无关的OCCC三组相比,后两组miR-20a-5p,93-5p,203a和328表达相近,均低于试验组癌。结论:内异症恶变的卵巢透明细胞癌研究中,miR-199b-5p,miR-200a-3p,miR-200b-3p,miR-20a-5p,miR-20b-5p,miR-106a-5p,miR-93-5p,miR-203a 和miR-328可能成为研究的关键miRNA。第二部分卵巢透明细胞癌的临床病理学特点与预后分析目的:卵巢透明细胞癌与子宫内膜异位症联系密切,本研究旨在研究卵巢透明细胞癌的临床病理特点,探究内异症是否为可能的预后因素。方法:回顾性分析对2000年到2016年在北京协和医院就诊的卵巢透明细胞癌患者的病历及病理资料,进行统计学数据处理。结果:共纳入264名卵巢透明细胞癌的患者,84(31.8%)名为内异症相关的卵巢癌(endometriosis associated ovarian cancer,EAOC),EAOC 组中根据是否符合Sampson和Scott标准又分为两个亚组,内异症恶变组(n=42,50%)和非恶变组(n=42,50%)。EAOC组发病年龄更小,多在绝经前诊断,无症状盆腔包块更多,早期(Ⅰ,Ⅱ)病例更多,更多合并子宫腺肌症,更易达到满意的肿瘤细胞减灭术;不合并内异症的对照组腹胀症状更多,更多合并腹水、LVSI阳性,复发率、死亡率更高;EAOC中两个亚组相比,非内异症恶变组复发率和死亡率更高,其他指标均无统计学差异。单变量生存分析中内异症与OS和DFS都相关,多变量分析中不是独立预后因素;多变量生存分析显示OS和DFS的独立预后因素一致,均为FIGO分期、残余肿瘤和LVSI。结论:合并内异症的卵巢透明细胞癌有其独特的临床病理特征,OS和DFS的独立预后因素均为FIGO分期、残余肿瘤和LVSI,内异症不是OS或DFS的独立预后因素。第三部分卵巢畸胎瘤合并抗N-甲基-D-天冬氨酸受体脑炎例临床病例分析目的:总结卵巢畸胎瘤合并抗N-甲基D-天冬氨酸受体(NMDAR)脑炎患者的临床特征。方法:收集北京协和医院和北京天坛医院2011年6月至2016年10月收治的21例卵巢畸胎瘤合并抗NMDAR脑炎患者的临床资料,对其临床表现、辅助检查、治疗及预后进行回顾性总结。结果:13例患者发病前有上呼吸道感染的前驱症状。临床多表现为典型精神症状、痫性发作和不自主运动。19例患者血清和脑脊液抗NMDAR抗体均为阳性,1例仅脑脊液抗NMDAR抗体阳性,1例血清和脑脊液抗NMDAR抗体均为阴性。卵巢畸胎瘤平均直径4cm,2例为双侧卵巢畸胎瘤,其余均为单侧;仅1例为未成熟畸胎瘤Ⅰ级,其余均为成熟畸胎瘤。经过卵巢畸胎瘤切除及免疫治疗,20例患者症状得到明显缓解。随访期间3例患者出现精神症状复发或肿瘤复发,无死亡病例。结论:卵巢畸胎瘤合并抗NMDAR脑炎常以神经及精神症状起病,容易被误诊为精神心理疾病,病毒性脑炎,或癫痫等;手术切除卵巢畸胎瘤结合免疫治疗多数预后良好。
[Abstract]:Part I study of miRNA expression profiles in ovarian hyaline cell carcinoma with malignant transformation of endometriosis: the purpose of this study was to use miRNA microarray gene chip technology (microarray) to treat endometriosis (hereinafter referred to as endometriosis) to ovarian clear cell carcinoma (ovarian clear cell carcinoma, OCCC) at all levels, including the pathological changes of endometriosis (microarray). The miRNA expression profiles of the intima, endometriosis, atypical endometriosis, atypical endometriosis, cancer, and the control group were compared, and the bioinformatics analysis was used to screen out the different miRNA and its possible target genes. The purpose was to find the biomarkers for the malignancy of the disease, and to further study the gene pathway and target therapy of the disease. Methods: microarray chip technology was used to study the miRNA expression profiles of 4 cases of ovarian hyaline cell carcinoma with malignant endometriosis and its control group. The enrichment analysis (GO-enrichment Analysis) of differential expression miRNA. for differentially expressed miRNA (GO-enrichment Analysis) and Pathway enrichment analysis (Pathway-enrichme) were screened. NT Analysis), miRNA and gene regulatory network (miRNA-Gene-Network), miRNA and pathway regulatory network (miRNA-pathway-Network) and other bioinformatics analysis, screening candidate miRNA. in 6 cases of verifying group pathological paraffin sections using real-time fluorescent quantitative PCR (RT-PCR) verification based on chip screening differential miRNA, in order to verify the chip expression profile Results: OCCC in endometriosis, endometriosis, atypical endometriosis and four stages of cancer, miR-199b-5p decreased from the eutopic endometrium to cancer, and the atypical endometriosis to cancer decreased significantly, and the expression of atypical endometriosis and cancer decreased significantly; the expression of miR-200a-3p and miR-200b-3p was bidirectional, with the eutopic endometrium as the control, and in the endometriosis and not A decrease in typical endometriosis and a rise in the cancer tissue. OCCC, a malignant transformation of endometriosis, conforms to ovarian cancer associated with endometriosis, but the OCCC in non endometriosis and OCCC three that are not associated with endometriosis, the latter two groups are similar in the expression of miR-20a-5p, 93-5p, 203A and 328, all lower than those in the experimental group. MiR-199b-5p, miR-200a-3p, miR-200b-3p, miR-20a-5p, miR-20b-5p, miR-106a-5p, miR-93-5p, miR-203a, and miR-328 may be the key miRNA. second part of the study of the clinicopathological features and prognostic analysis of ovarian clear cell carcinoma: ovarian clear cell carcinoma is closely associated with endometriosis. This study aims to study ovarian permeability. The clinicopathological features of the cancer of the clear cell and the possible prognostic factors of endometriosis. Methods: a retrospective analysis of the medical records and pathological data of ovarian clear cell carcinoma patients in Peking Union Medical College Hospital from 2000 to 2016. Results: 264 patients with ovarian clear cell carcinoma were admitted to 84 (31.8%) names. Endometriosis associated ovarian cancer (EAOC) was associated with endometriosis. The EAOC group was divided into two subgroups according to the Sampson and Scott standards. The onset age of the group (n=42,50%) and the non malignant group (n=42,50%).EAOC group was smaller, more before the menopause, more in the asymptomatic pelvic masses, and in the early (I, II) disease. More patients with adenomyosis, more likely to achieve satisfactory tumor cell reduction, more abdominal distention in the control group without endometriosis, more amalgamated ascites, LVSI positive, a higher recurrence rate, and higher mortality; the relapse rate and mortality rate in the two subgroups of EAOC were higher, and the other indexes were not statistically different. In the variable survival analysis, the disease was related to both OS and DFS. Multivariate analysis was not an independent prognostic factor. Multivariate survival analysis showed that the independent prognostic factors of OS and DFS were consistent with FIGO staging, residual tumor and LVSI. conclusion: ovarian clear cell carcinoma with endometriosis had its unique clinicopathological features, independent prognosis of OS and DFS. All factors are FIGO staging, residual tumor and LVSI, and endometriosis is not an independent prognostic factor for OS or DFS. Third ovarian teratoma combined with anti N- methyl -D- aspartic receptor encephalitis Objective: To summarize the clinical characteristics of ovarian teratoma with anti N- methyl D- aspartic acid receptor (NMDAR) encephalitis patients. Methods: collect Beijing The clinical data of 21 cases of ovarian teratoma with anti NMDAR encephalitis treated from June 2011 to October 2016 in Union Hospital and Beijing Tiantan Hospital were reviewed. The clinical manifestations, auxiliary examination, treatment and prognosis were reviewed. Results: 13 patients had premonitory symptoms of upper respiratory tract infection. The clinical manifestations were typical mental symptoms. Both serum and cerebrospinal fluid anti NMDAR antibody were positive in.19 patients with epileptic seizures and involuntary movement, 1 cases of cerebrospinal fluid anti NMDAR antibody positive, 1 cases of serum and cerebrospinal fluid anti NMDAR antibody negative. The average diameter of ovarian teratoma was 4cm, 2 cases were bilateral ovarian teratoma and the rest were unilateral; only 1 cases were immature teratoma grade I, the rest were all For the mature teratoma. After the resection of ovarian teratoma and immunotherapy, the symptoms of 20 patients were obviously relieved. During the follow-up period, 3 patients had recurrent mental symptoms or tumor recurrence and no death. Conclusion: ovarian teratoma combined with anti NMDAR encephalitis often occurs with neurological and mental symptoms and is easily misdiagnosed as psycho psychological disease and viral Encephalitis, or epilepsy, etc., surgical resection of ovarian teratoma combined with immunotherapy has a good prognosis.

【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】：R711.71;R737.31

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