颅内生殖细胞肿瘤患者脑脊液差异蛋白组学研究

发布时间：2018-03-07 20:34

本文选题：垂体柄增粗　切入点：垂体功能减退症　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

【摘要】：第一部分垂体柄增粗患者的临床特征和病因研究目的:总结导致垂体柄增粗(pituitary stalk thickness,PST)的疾病谱和临床特点,以提高临床诊疗水平。方法:回顾性分析北京协和医院2014年1月至2017年5月收治的PST患者临床资料,归纳总结其临床特征及病因。结果:共纳入322例PST患者,女性和男性患者分别为178例(55.3%)和144例(44.7%),中位诊断年龄29.0岁(范围:3.0-83.0岁),20岁以下青少年患者占32.9%。尿崩症是最常见的首发症状,占所有PST患者的59.3%,69.3%患者出现至少一种垂体激素低减。相比于单纯垂体柄受累者,同时累及垂体柄和下丘脑的患者发生全垂体功能减退症的风险更高(垂体柄+下丘脑+垂体:OR=14.0,p0.001;垂体柄+下丘脑:OR=13.4,p0.001)。133例(41.3%)患者最终明确病因诊断,其中肿瘤(72例,22.4%)、炎症浸润(40例,12.4%)以及先天性疾病(16例,5.0%)是最主要原因,青少年以颅内生殖细胞肿瘤(65.9%)最常见,成人以朗格汉斯细胞组织细胞增生症(16.9%)和恶性肿瘤转移(15.7%)最常见。病灶范围是预测恶性肿瘤的独立预测因子(p0.01)。在有随访资料的54例原因不明的PST患者中,经平均随访时间11.7±7.6个月,15例(27.8%)患者PST完全恢复正常,8例(14.8%)垂体柄较前变细,27例(50.0%)垂体柄病变稳定,4例(7.4%)患者垂体柄进行性增粗。成年患者的自发缓解概率显著高于青少年患者(p=0.050)。结论:PST是一组异质性很高的疾病,肿瘤、炎症、先天性疾病是最常见的原因。各病因在临床表现及影像学特征上难以区分,需长期动态观察垂体MRI变化,必要时需病理活检明确诊断。第二部分颅内生殖细胞肿瘤患者脑脊液差异蛋白组学研究目的:探索脑脊液蛋白质组学在颅内生殖细胞肿瘤临床诊断中的价值,寻找潜在的脑脊液诊断标记物。方法:以北京协和医院2013年11月至2017年4月收治的21例颅内生殖细胞肿瘤患者为研究组,以同期收治的确诊为其他疾病的9例垂体柄增粗患者为对照组,采用Orbitrap数据非依赖采集(data independent acquisition,DIA)液相色谱串联质谱(liquid chromatography tandem mass spectrometry,LC-MS/MS)技术,进行脑脊液差异蛋白分析,并与组织差异蛋白组研究结果进行比较分析。采用免疫组化方法研究组织蛋白组学发现的差异蛋白p-Akt(Ser 473)、p-mTOR(Ser2448)、PTEN在颅内生殖细胞瘤组织中的表达情况。结果:各脑脊液样本中可定量的蛋白质平均种类数为1002±131种。比较纯生殖细胞瘤/对照组,以丰度变化2倍、p值0.05为标准筛选差异蛋白,共得到23种脑脊液差异蛋白,包括13种上调蛋白和10种下调蛋白。ROC曲线分析提示,其中21种差异蛋白对诊断颅内纯生殖细胞瘤有预测价值(p0.05),而CHST10、PCDHGC5、MANSC1、PCDH10、BAI1、NLGN2、CX3CL1、CDH8、F13B、C5、MIA 的曲线下面积达 0.9 以上(p0.05)。FAT2、BAI1、TAC1、NLGN2、LBP、IGKV3-20是独立于年龄、性别的指标(p0.05)。FAT2升高与肿瘤播散有相关趋势(p=0.089)。p-Akt(Ser473)在颅内生殖细胞瘤的肿瘤细胞胞浆与胞核呈弱阳性表达,在间质及淋巴细胞中不表达。p-mTOR(Ser2448)在肿瘤细胞和淋巴细胞中均有表达。PTEN在肿瘤细胞和淋巴细胞均有表达,且以后者为主。结论:脑脊液差异蛋白有希望成为鉴别颅内生殖细胞瘤和其他垂体柄病变的潜在标记物。
[Abstract]:The first part of pituitary stalk to the clinical features and etiology of rough patients: summary lead to pituitary stalk thickening (pituitary stalk, thickness, PST) of the disease spectrum and clinical features, to improve the level of clinical diagnosis and treatment. Methods: a retrospective analysis of clinical data of PST patients in Peking Union Medical College Hospital from January 2014 to May 2017, to summarize the clinical features and etiology results: totally 322 patients with PST, female and male patients were 178 cases (55.3%) and 144 cases (44.7%), the median age of diagnosis 29 years old (range: 3.0-83.0 years), young people under the age of 20 years accounted for 32.9%. patients with diabetes insipidus was the most common symptom, accounting for 59.3% of all patients with PST, 69.3% patients had at least one pituitary hormone decreased. Compared with pituitary stalk involvement, involved the pituitary stalk and hypothalamus risk in patients with panhypopituitarism higher (+ + vertical hypothalamic pituitary stalk Body: OR=14.0, p0.001; hypothalamus pituitary stalk +: OR=13.4, p0.001).133 cases (41.3%) patients eventually clear etiology diagnosis, tumor (72 cases, 22.4%), inflammation (40 cases, 12.4%) and congenital diseases (16 cases, 5%) is the main reason that teenagers with intracranial germ cell tumors (65.9%) the most common adult Langerhans cell histiocytosis (16.9%) and malignant tumor (15.7%). The most common lesion range is independent predictor of malignant tumor (P0.01). In 54 cases of unknown reason with follow-up data of PST patients, the mean follow-up time was 11.7 + 7.6 months (27.8%), 15 cases of PST patients recovered completely, 8 cases (14.8%) of pituitary stalk than before thinning, 27 cases (50%) of pituitary stalk stable disease, 4 cases (7.4%) of patients with pituitary stalk thickening. Spontaneous remission in adult patients was significantly higher than the probability of young patients (p=0.050). Conclusion: PST is a group of heterogeneous High disease, tumor, inflammation, congenital disease is the most common cause. The etiology characteristics in the clinical manifestation and image it is difficult to distinguish, need long-term dynamic observation of pituitary MRI change, when necessary to biopsy diagnosis. The second part is the research of intracranial germ cell tumors in patients with cerebrospinal fluid protein group objective: Study of proteomics in the clinical diagnosis of intracranial germ cell tumors for the value of cerebrospinal fluid potential diagnostic marker. Methods: the study group with 21 cases of intracranial germ cell tumor patients in Peking Union Medical College Hospital from November 2013 to April 2017 were treated with the same period, 9 cases were diagnosed as pituitary stalk thickening in patients with other diseases as control group using Orbitrap, data dependent acquisition (data independent acquisition, DIA) liquid chromatography tandem mass spectrometry (liquid chromatography tandem mass spectrometry, LC-MS/MS). Operation, analysis of cerebrospinal fluid proteins, and compared with the results of tissue protein group difference analysis. Immunohistochemical method was used to study the tissue proteome found differences in protein p-Akt (Ser 473), p-mTOR (Ser2448), PTEN in intracranial germ cell tumors. The expression of the quantitative protein the average number of each species in CSF samples was 1002 + 131. Compared to pure germ cell tumor / control group, to changes in the abundance of 2 times, P value of 0.05 for the standard screening of differentially expressed proteins, 23 proteins in cerebrospinal fluid were obtained, including 13 up-regulated proteins and 10 down regulated protein.ROC curve analysis showed that the 21 kinds of difference pure protein in the diagnosis of intracranial germ cell tumors have predictive value (P0.05), CHST10, PCDHGC5, MANSC1, PCDH10, BAI1, NLGN2, CX3CL1, CDH8, F13B, C5, MIA curve below product of more than 0.9 (P0.05).FAT2, BAI1, TAC1, NLGN2, LBP, IGKV3-20 is the only In the age, gender index (P0.05) increased.FAT2 related trends and tumor spread (p=0.089).P-Akt (Ser473) showed weakly positive expression in intracranial germ cell tumors of the cytoplasm of tumor cells and nuclei, the expression of.P-mTOR in mesenchymal and lymphocytes (Ser2448) in tumor cells and lymphocytes expressed.PTEN in both tumor cells and lymphocytes, and the latter mainly. Conclusion: the difference of cerebrospinal fluid protein might become a potential marker for differential diagnosis of intracranial germ cell tumors and other lesions of the pituitary stalk.

【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】：R739.41

【相似文献】