凋亡抑制基因bcl-2在弥漫性大B细胞淋巴瘤中的表达及其临床意义

摘要

目的 探讨凋亡抑制基因bcl-2在弥漫性大B细胞淋巴瘤(DLBCL)不同免疫亚型中的表达,以及bcl-2蛋白表达对患者生存期的影响.方法 应用免疫组织化学(EliVision plus和PV-9002法)对214例DLBCL进行CD10、bcl-6、MUM-1、bcl-2及NF-κB检测,采用Hans免疫分型方法将DLBCL分为生发中心B细胞(GCB)型和非GCB型;荧光原位杂交(FISH)技术检测IgH/bcl-2易位及bcl-2扩增.结果 214例DLBCL中,GCB型66例(30.8%),非GCB型148例(69.2%).bcl-2蛋白阳性106例(49.5%),其中在非GCB型中比率(59.5%,88/148)较GCB型中比率(27.3%,18/66)差异具有统计学意义(P<0.01);发生IgH/bcl-2易位仅有8例(3.7%),其中6例发生在GCB型(9.1%),2例发生在非GCB型(1.4%),差异具有统计学意义(P<0.05);出现bcl-2扩增113例(52.8%),在GCB型中发生率40.9%(27/66)低于非GCB型58.1%(86/148),差异具有统计学意义(P<0.05).非GCB型中bcl-2蛋白表达与NF-κB表达、bcl-2基因扩增均呈正相关(r=0.216和0.219,均P<0.05),但这种相关性在GCB型未体现.bcl-2表达者生存期更短,对应中位生存时间为(31.4±3.8)个月,而不表达者则为(40.2±4.2)个月;当与DLBCL免疫学类型及临床分期结合评估时,bcl-2表达者的校正危险度比不表达者增加1.89倍.结论 本组DLBCL以预后较差的非GCB型占多数,其遗传学改变以高频率bcl-2基因扩增和低频率IgH/bcl-2易位为特征;bcl-2蛋白表达主要发生在非GCB型,其机制涉及bcl-2基因扩增及NF-κB活化.bcl-2蛋白表达患者生存期短,死亡危险度较高,可以作为独立于临床分期和免疫类型的DLBCL预后因子.%Objective To evaluate the molecular mechanism and prognostication of bcl-2 protein expression in different subgroups of diffuse large B-cell lymphoma(DLBCL) in Guangxi Zhuang Autonomous Region, China. Methods Immunohistochemical stains for CD10,bcl-6,MUM-1,bcl-2 and NF-κB were performed in 214 cases of DLBCL. The Hans immunologic classification was applied to classify DLBCL into GCB and non-GCB subgroups. Using a dual-probe fluorescence in-situ hybridization(FISH) assay, IgH/bcl-2 gene translocation and bcl-2 amplification were analyzed. Results In 214 cases of DLBCL, 30.8%(66/214)of cases were GCB and 69.2%(148/214) were non-GCB. Twenty-seven point three percent(18/66) of GCB subgroups and 59.5%(88/148)of non-GCB subgroups had bcl-2 protein expression,with a significant difference (P<0.01). IgH/bcl-2 translocation was positive in 3.7%(8/214) of cases,even majority of them(6/8) was found in GCB subgroup,while represented only 9.1% of GCB case. There was a significant difference(P=0.02)in bcl-2 gene amplification between GCB (27/66, 40.9%) and non-GCB subgroup(86/148,58.1%). Among non-GCB cases, the expression of bcl-2 was correlated with that of NF-κB expression and bcl-2 gene amplification (r=0.216 and 0.219,respectively,P<0.05). No similar correlation was observed in GCB cases. The overall survival time of bcl-2-positive patients (31.4±3.8) months was shorter than that of bcl-2-negative patients (40.2±4.2) months. In conjunction with immunophenotypes and clinical stages, the bcl-2 positive patients had a 1.89 times higher risk than that of the bcl-2 negative patients. ConclusionsMajority of the cases were prognostically unfavorable non-GCB subgroups among DLBCL, which were characterized by high frequency of bcl-2 gene amplification and low frequency of IgH/bcl-2 translocation. The anti-apoptotic gene bcl-2 was frequently expressed in non-GCB subgroups and closely related to the gene amplification and NF-κB activation. bcl-2 positive patients had more short overall survival times, would face significant higher risk of death, these results suggested that bcl-2 could be a prognostic marker independent to clinical staging and immunophenotyping.