子宫内膜异位症相关卵巢癌临床特点和恶变机制的研究

发布时间：2018-06-08 16:35

本文选题：子宫内膜异位症相关卵巢癌 + 预后　；参考：《北京协和医学院》2016年博士论文

【摘要】：目的子宫内膜异位症虽为最常见妇科良性疾病之一,但其具有一定恶变能力,且与卵巢透明细胞癌和子宫内膜样癌的发生存在密切关系,因而学界提出了“内异症相关卵巢癌”的概念,并认为这是一类具有特殊起源、发生、临床和预后表现的卵巢上皮性肿瘤。本研究回顾性分析背景协和医院卵巢透明细胞癌和子宫内膜样癌患者的就诊资料,探讨合并内异症的上述卵巢癌患者与未合并内异症患者间差异,旨在揭示内异症相关卵巢癌的临床预后特点。方法收集1988年至2012年在北京协和医院妇产科就诊的总计309例卵巢透明细胞癌和子宫内膜样癌病例,回顾性分析其临床资料,包括术前临床信息、手术病理信息和术后化疗情况,并进行随访调查及生存分析,应用Kaplan-Meier单因素分析筛选与预后相关危险因素,并用Cox比例风险模型进行多因素分析以发掘影响预后的独立因素,总结其临床预后特点。结果回顾性病例分析结果显示内异症相关卵巢透明细胞癌和子宫内膜样癌较一般卵巢癌具有更早的发病年龄、更多绝经前期状态、更低术前CA125水平、更低肿瘤分期、更高手术切净几率、更低的死亡率和复发率。单因素生存分析显示年龄、月经状态、肿瘤分期、手术是否切净、组织学类型及是否合并内异症对卵巢透明细胞癌和子宫内膜样癌预后有影响。多因素分析显示月经状态和肿瘤分期是影响卵巢透明细胞癌和子宫内膜样癌总体生存率的独立因素,肿瘤分期和手术是否切净是影响无病生存率的独立因素,而是否合并内异症不是影响卵巢透明细胞癌和子宫内膜样癌预后的独立因素。结论内异症相关卵巢透明细胞癌和子宫内膜癌患者较普通透明细胞癌及卵巢癌患者具有独特的临床特点及更好的预后。内异症本身并非影响透明细胞癌和子宫内膜样癌预后的独立因素。目的子宫内膜异位症相关卵巢癌与一般卵巢癌相比具有不同的临床和预后特点,提示它们之间可能有两种截然不同的组织来源和发生方式。一系列针对内异症恶变机制的多角度研究认为这是一个由氧化应激、炎症因子、性激素调控等多种复杂因素共同作用,经过漫长演变和转化的过程,而一些重要的分子生物学改变可能在其中起关键驱动作用。本研究旨在通过全外显子测序技术分析比较经内异症恶变的卵巢子宫内膜样癌病例不同病变阶段内分子水平改变差异,寻找恶变过程中的潜在驱动基因,以期探索子宫内膜异位症恶变的发生机制。方法我们通过查询内异症合并卵巢子宫内膜样癌病例,复核其手术病理,根据Sampson及Scott诊断标准筛选由内异症恶变的卵巢子宫内膜样癌患者,经激光捕获显微切割精确获取其卵巢良性异位内膜、卵巢不典型异位内膜和卵巢子宫内膜样癌的石蜡病理标本,提取基因组DNA并进行全外显子组测序。通过比对不同病变阶段组织内外显子突变差异,寻找其中潜在的关键突变基因。结果全外显子组测序在卵巢良性异位内膜、不典型异位内膜和子宫内膜样癌DNA样本中分别检测到57911、18768和69001个单核苷酸突变(SNV)或段片段插入缺失(InDel),通过无功能突变和数据库信息比对高频突变过滤,在卵巢不典型内异症组织和内膜样癌组织中共发现21个相同外显子突变,其中CDKN2AIP、UIMC1和TPBG基因分别参与调控细胞增殖凋亡抉择、DNA损伤修复和Wnt信号通路。结论全外显子组测序证实卵巢不典型内异症和卵巢子宫内膜样癌间存在相同突变基因,其中CDKN2AIP、UIMC1和TPBG等基因中某个或多个可能是内异症恶变至子宫内膜样癌过程的潜在驱动基因。
[Abstract]:Objective endometriosis is one of the most common benign gynecologic diseases, but it has a certain malignant ability, and is closely related to the occurrence of ovarian clear cell carcinoma and endometrioid carcinoma. Therefore, the concept of "endometriosis related ovarian cancer" is proposed by the academic community, and it is considered as a class of special origin, occurrence, clinical and prognosis. The present study reviewed the clinical data of patients with ovarian clear cell carcinoma and endometrioid carcinoma in the background Concorde and hospital, explored the differences between the ovarian cancer patients with endometriosis and the patients with unincorporated endometriosis, and aimed at revealing the clinical prognostic characteristics of nests associated with endometriosis. Methods collected from 1988 to 1988. A total of 309 cases of ovarian clear cell carcinoma and endometrioid carcinoma in the Department of Obstetrics and gynecology in Peking Union Medical College Hospital in 2012 were reviewed. The clinical data were analyzed retrospectively, including preoperative clinical information, surgical pathology information and postoperative chemotherapy, follow-up investigation and survival analysis. Kaplan-Meier single factor analysis should be used to screen the risk of prognosis. Risk factors, and multifactor analysis using the Cox proportional hazard model to explore independent factors that affect prognosis and summarize their clinical prognostic characteristics. Results retrospective case analysis showed that endometriosis related ovarian clear cell carcinoma and endometrioid carcinoma have earlier age of onset, more premenopausal status, lower operation than general ovarian cancer. Anterior CA125 level, lower tumor staging, higher surgical removal rate, lower mortality and recurrence rate. Univariate survival analysis showed that age, menstrual state, tumor staging, surgical removal, histologic type, and combination of endometriosis have an impact on the prognosis of ovarian clear cell carcinoma and endometrioid carcinoma. State and tumor staging are independent factors affecting the overall survival rate of ovarian clear cell carcinoma and endometrioid carcinoma. Tumor staging and surgical removal are independent factors affecting the disease free survival, and whether or not endometriosis is not an independent factor affecting the prognosis of ovarian clear cell carcinoma and endometrioid carcinoma. Nests of clear cell carcinoma and endometrial cancer have unique clinical characteristics and better prognosis than those of common clear cell and ovarian cancer. The characteristics of bed and prognosis suggest that there may be two distinct sources and ways of formation between them. A series of studies on the mechanism of malignancy of endometriosis are considered to be a complex factor, such as oxidative stress, inflammatory factors, sex hormone regulation and other complex factors, through a long process of evolution and transformation, and some important factors. Molecular biological changes may play a key driving role in this study. The aim of this study is to compare the difference in molecular level changes during different pathological stages of ovarian endometrioid carcinoma cases with malignant changes of endometriosis by exon sequencing and search for potential driving genes in the process of malignancy in order to explore the malignancy of endometriosis. Methods we reviewed the cases of endometrioid endometrioid carcinoma with endometriosis and reviewed its operation and pathology. According to the Sampson and Scott diagnostic criteria, we screened the ovarian endometrioid carcinoma patients with endometriosis and malignancy. The benign ectopic endometrium, the atypical ectopic endometrium and the ovaries of the ovaries were obtained by laser microdissection. The paraffin pathological specimens of endometrioid carcinoma of the nested endometrium were extracted from the genomic DNA and sequenced the exon group. The potential key mutations were found by comparing the differences of the intron and inside intron mutations at different pathological stages. Results the exon group was sequenced in the ovarian benign ectopic endometrium, atypical ectopic endometrium and endometrioid carcinoma DNA samples. 5791118768 and 69001 single nucleotide mutations (SNV) or segment insertion deletion (InDel) were detected, and 21 identical exons were found in the atypical endometrium and endometrioid carcinoma tissues by non functional mutation and database information, and 21 of the same exons were found in the atypical endometrium and endometrioid carcinoma tissues, including CDKN2AIP, UIMC1 and TPBG genes, respectively. The choice of cell proliferation and apoptosis, DNA damage repair and Wnt signaling pathway. Conclusion all exon sequencing confirms that the same mutations exist between ovarian atypical endometrioid and ovarian endometrioid carcinomas, and one or more of CDKN2AIP, UIMC1 and TPBG may be the potential driving force for endometrioid carcinoma. Genes.
【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】：2016
【分类号】：R711.71;R737.31

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