發(fā)布時間：2018-05-18 10:12

  本文選題：套細胞淋巴瘤 + P53缺失��； 參考：《北京協(xié)和醫(yī)學(xué)院》2016年碩士論文

【摘要】：背景：套細胞淋巴瘤是一種典型的非霍奇金淋巴瘤,約占非霍奇金淋巴瘤淋巴瘤病患的6%。套細胞淋巴瘤作為一種難治療,不易治愈的疾病。中位生存約僅3年。目前隨著新的檢測技術(shù)的出現(xiàn)及應(yīng)用,人們對MCL淋巴瘤的發(fā)病機制有著更深的認識及理解。套細胞淋巴瘤是B細胞淋巴瘤的一種亞類,由于來源于生發(fā)中心前的B細胞,所以表達細胞表面抗原CD5, CD20等細胞表面標志,該區(qū)細胞來源位置存在于正常濾泡的生發(fā)中心。套細胞淋巴瘤由于染色體11和14號的異位,導(dǎo)致過度表達cyclinD 1蛋白。染色體的具體異位位置存在于t(11；14)(q13；q32)。而熒光原位雜交技術(shù)作為一種細胞遺傳學(xué)技術(shù),使用熒光探針檢測大片段基因的缺失。目的：通過熒光原位雜交的方法分析患者的TP53缺失對侵襲性套細胞淋巴瘤患者預(yù)后的影響,并且研究侵襲性套細胞淋巴瘤患者P53缺失發(fā)生的同時,探索熒光原位雜交檢測其它位點的生物學(xué)特性在病人預(yù)后的意義。方法：回顧分析中國醫(yī)學(xué)科學(xué)院血液病醫(yī)院2003年7月至2015年1月間50例伴外周血及骨髓侵犯的套細胞淋巴瘤患者資料。并且使用熒光原位雜交的方法檢測患者D13S25/13q14、ATM/11q22、p53/17p13、c-MYC/8q24、BCL2/18q21和IGH/CCND1/t(11;14)共6種DNA探針,分析遺傳學(xué)相關(guān)性及預(yù)后的影響。結(jié)果：患者的中位年齡為55.5歲,其中38例患者為男性,18例患者伴有B癥狀,36例(72%)患者在初診時伴有脾大癥狀。中位白細胞(WBC)計數(shù)為44.73(2.63-193.78)×109/L,中位82微球蛋白為4.45(1.95 to12.7)mg/L。基于MCL國際預(yù)后積分(MIPI)系統(tǒng),26例(52%)患者為高危組,中危組和低危組各12例患者(24%)。通過SPSS單變量分析PFS和OS預(yù)后因素與各檢測位點的關(guān)系后發(fā)現(xiàn),De113q、 De117p、MYC擴增或者獲得都對PFS和OS具有統(tǒng)計學(xué)意義,其中Del 13q對PFS和OS的P值結(jié)果分別是0.003,0.012,Del 17p對PFS和OS的P值分別是0.000,0.000,MYC擴增或者獲得對PFS和OS的P值影響分別是0.000,0.000：多變量分析各因素與PFS和OS的關(guān)系發(fā)現(xiàn)Del 17、MYC擴增或者獲得這兩個因素對其具有獨立的預(yù)后意義。其中Del 17的PFS和OS P值分別是0.039,0.045；MYC獲得和擴增對PFS和OS的P值分別是0.020,0.026。結(jié)論：P53缺失在套細胞淋巴瘤患者中作為常見的細胞突變,在患者預(yù)后中對PFS和OS具有獨立預(yù)后因素。在成熟B細胞淋巴瘤中,MYCW及BCL2重排的發(fā)生率及其預(yù)后意義己被深入研究,但在發(fā)病率較低的套細胞淋巴瘤(MCL)中研究尚少。本研究在50例伴有骨髓侵犯的MCL患者中應(yīng)用英光原位雜交(FISH)技術(shù)檢測了MYC、BCL2及其他細胞遺傳學(xué)異常,結(jié)果顯示18例患者G6%)伴有MYC獲得和/或擴增,12例患者(24.0%)伴有BCL2獲得和/或擴增。在18例伴有MYC異常的患者中有4例同時伴有MYC易位,但在伴有BCL2遺傳學(xué)異常的患者中并未檢測到BCL2易位。僅有2例患者(4.0%)同時伴有MYC和BCL2異常。合并MYC異常的患者其腫瘤負荷顯著增高,并且相較于不伴MYC異常的患者而言,其MIPI中高危組患者比例更高,遺傳學(xué)不穩(wěn)定性也更高。但伴有BCL2異常的患者其臨床特征或細胞遺傳學(xué)特征相較于不伴該異常的患者并無統(tǒng)計學(xué)差異。伴MYC異常的患者其無進展生存期(PFS)和總體生存期(OS)均顯著縮短(PFS9.0VS.48.0個月,P=000;OS 12.0 VS.94.5個月,p=.000),但BCL2異常對PFS和OS的影響并無統(tǒng)計學(xué)意義。多因素分析顯示,MYC異常是PFS和OS的獨立預(yù)后不良因素,并且強化治療方案并不能改善這部分患者預(yù)后。因此,在MCL患者中MYC異常為預(yù)后不良因素,而伴有BCL2異常與不良預(yù)后并無相關(guān)性,對這部分患者亟待新的治療方式病人情況和實驗方法:2003年6月至2015年1月,50例伴有骨髓侵犯的MCL淋巴瘤患者就診于中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)院血液病醫(yī)院。所有入組患者均知情同意,該項目同時被審查委員會批準。該研究中基本的病例記錄資料包括性別,年齡,體能狀況,Ann Arbor分期,外周淋己結(jié)所在區(qū)域,染色體核型,骨髓和外周血形態(tài),細胞免疫表型,乳酸脫氨酶水平,W及治療方案和臨床療效。病理組織樣品的評估由兩位位病理醫(yī)師(同時也是本文中的作者)依據(jù)WHO分類明確診斷。所有骨髓組織標本均取至患者初診時。此項研究由中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院的倫理委員會支持。熒光原位雜交(FISH)通過FISH分析樣品的常規(guī)核型。DNA探針的組合包括探針13ql4.3(LSI D13S25和RB-1),14q32(LSIIGHC/IGHV),17pl3(LSIp53),llq22(LSIATM),LSI BCL2(18q32)和MYC(8q24),為雙色,雙分離重排探針,而IGH/BCL2為雙色雙融合異位探針,并且LSI IGH/MYC/CEP8為3色雙融合探針,CCND1/IGH為雙色雙融合異位探針。所有的探針從美國的Vysis購置。根據(jù)生產(chǎn)廠家推薦完成樣品準備及前期處理PS1。信號的檢出至少根據(jù)200個細胞信號得出。陽性cutoff值(正常對照的平均值+3標準差)來自10個遺傳學(xué)正常的人的樣品,其中Rb-1,ATM和PW的界值為6.5%;IG比BCL2和CCND1/IGH異位雙色雙融合探針的為4.5%;而LSIIGH,MYC,CEP8H色雙融合探針的也為4.5%�？截悢�(shù)獲得定義為本研究中的基因具有S個拷貝,然而拷貝數(shù)的擴增被定義為至少4個拷貝。
[Abstract]:Background: cell lymphoma is a typical non Hodgkin lymphoma, which accounts for the 6%. cell lymphoma of non Hodgkin lymphoma's lymphoma as a refractory, untreatable disease. The median survival is about 3 years. With the emergence and application of new detection techniques, the pathogenesis of MCL lymphoma is deeper. The cell lymphoma is a subclass of B cell lymphoma, which is derived from the B cells before the germinal center, so it expresses the surface antigen of the cell surface antigen CD5, CD20 and other cell surface markers. The cell origin of this area exists in the germinal center of the normal follicular. The specific location of cyclinD 1 protein is expressed. The specific location of chromosomes exists in t (11; 14) (q13; q32). Fluorescence in situ hybridization is used as a cytogenetic technique to detect the deletion of large fragment genes by fluorescence probe. Objective: to analyze the deletion of TP53 in patients with invasive cell lymphoma by fluorescence in situ hybridization. The effect of the prognosis and the study of the P53 deletion in patients with invasive nested cell lymphoma, and the significance of exploring the biological characteristics of other loci by fluorescence in situ hybridization in the patient's prognosis. Methods: a retrospective analysis of 50 cases of peripheral blood and bone marrow invasion from July 2003 to January 2015 of the Chinese Academy of Medical Sciences. D13S25/13q14, ATM/11q22, p53/17p13, c-MYC/8q24, BCL2/18q21 and IGH/CCND1/t (11; 14) were used to detect the effects of 6 kinds of DNA probes on genetic correlation and prognosis. Results: the median age of patients was 55.5 years old, of which 38 were male and 18 patients were accompanied with B. Symptoms, 36 (72%) patients had splenomegaly symptoms at first visit. Median leukocyte (WBC) count was 44.73 (2.63-193.78) x 109/L, median 82 microglobulin was 4.45 (1.95 to12.7) mg/L. based on MCL international prognostic integral (MIPI) system, 26 (52%) patients were at high risk group, and 12 patients in middle and low risk groups (24%). PFS and OS were analyzed by SPSS univariate. After the relationship between the prognostic factors and the detection sites, it is found that De113q, De117p, MYC amplification or OS have statistical significance for PFS and OS, in which the P values of Del 13q are 0.003,0.012 on PFS and OS, respectively. The quantitative analysis of the factors associated with PFS and OS found that Del 17, MYC amplification or acquisition of these two factors had independent prognostic significance. The PFS and OS P values of Del 17 were 0.039,0.045, respectively, and MYC obtained and amplified for PFS and OS as common cells in patients with cell lymphoma. Mutations have independent prognostic factors for PFS and OS in patient's prognosis. The incidence of MYCW and BCL2 rearrangement in mature B cell lymphoma and its prognostic significance have been studied, but few studies have been made in the low incidence of nested cell lymphoma (MCL). In this study, 50 cases of MCL patients with bone marrow invasion (FISH) were used in this study. MYC, BCL2, and other cytogenetic abnormalities were detected in 18 patients with MYC acquisition and / or amplification. 12 patients (24%) were accompanied by BCL2 acquisition and / or amplification. In 18 patients with MYC abnormalities, 4 were accompanied by MYC translocation, but no BCL2 translocation was detected in patients with BCL2 abnormality. Only 2 were detected. Patients (4%) were accompanied by MYC and BCL2 abnormalities. The tumor load in patients with MYC abnormalities was significantly higher, and compared to those with no MYC abnormalities, the high risk groups in MIPI were higher in proportion and higher in genetic instability. There was no statistically significant difference in the patient's patients with MYC abnormalities (PFS) and overall survival (OS) significantly shortened (PFS9.0VS.48.0 months, P=000; OS 12 VS.94.5 months, p=.000), but the effect of BCL2 abnormality on PFS and OS was not statistically significant. And strengthening the treatment regimen does not improve the prognosis of this part of the patient. Therefore, in MCL patients, MYC is abnormal as a prognostic factor, and there is no correlation between abnormal BCL2 and poor prognosis. In this part of the patients, new treatment methods and experimental methods are urgently needed: 50 cases of MCL lymphoma with bone marrow invasion from June 2003 to January 2015. The patients were admitted to the hospital of Hematology in Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences. All the patients were informed consent. The project was approved by the review committee. The basic case records included sex, age, physical status, Ann Arbor staging, the area of the peripheral gage, chromosome karyotype, bone marrow and peripheral blood. State, cellular immunophenotype, lactate deaminase level, W and therapeutic regimen and clinical efficacy. The evaluation of pathological tissue samples was made by two position pathologists (and the author in this article) based on WHO classification. All bone marrow specimens were taken to the initial diagnosis of the patients. This study was conducted by the Beijing Academy of Medical Sciences of the Chinese Academy of Medical Sciences. The ethics committee supports the combination of fluorescent in situ hybridization (FISH) through FISH analysis of the conventional karyotype.DNA probes, including probe 13ql4.3 (LSI D13S25 and RB-1), 14q32 (LSIIGHC/IGHV), 17pl3 (LSIp53), llq22, double separation and rearrangement probes. I IGH/MYC/CEP8 is a 3 color dual fusion probe, and CCND1/IGH is a dual color dual fusion probe. All probes are purchased from the Vysis in the United States. The detection of PS1. signals for sample preparation and preprocessing according to the manufacturer's recommendation is at least according to 200 cell signals. The positive cutoff value (the average value of the normal control, +3 standard deviation) comes from 10 heredity. Samples of normal people, of which the boundary value of Rb-1, ATM and PW is 6.5%; IG is 4.5% for the heterotopic double color dual fusion probe of BCL2 and CCND1/IGH; while LSIIGH, MYC, and CEP8H dual fusion probes are also defined as S copies of the genes in this study, but the amplification of copies is defined as at least 4 copies.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R733.1

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