弥漫性大B细胞淋巴瘤各分子亚型中的bcl-6基因重排与蛋白表达的临床意义

目的 探讨弥漫性大B细胞淋巴瘤(DLBCL)各分子亚型中的bel-6基因重排、蛋白表达情况及其临床病理意义.方法 运用组织芯片技术,通过荧光原位杂交(FISH)技术对149例DLBCL组织中bcl-6基因重排进行检测,应用免疫组织化学技术(EnVision法)检测bcl-6以及细胞增殖指标Ki-67、细胞周期蛋白(cyclin)D3、p27Kill及Geminin等蛋白表达水平;结合临床病理资料,分析它们之间的相关性.结果 149例DLBCL可被分成3个分子亚型,其中4J0例为生发中心B细胞样(GCB样)亚型,75例为活化的非生发中心B细胞样(ABC样)亚型,34例为Type 3亚型.有118例成功进行了FISH检测,33例可检测到bcl-6基因重排,阳性率为28.0%.其中35.5%(22/62)的ABC样亚型DLBCL呈现bcl-6基因重排;较GCB样亚型(6/31,19.4%)和Type 3亚型(5/25,20.0%)的bcl-6基因重排高(P=0.160).在绝大部分(26/33,78.8%)有bcl-6基因重排的DLBCL中,伴随有bcl-6蛋白的过度表达,明显高于无bcl-6基因重排的病例(53/84,62.4%,P=0.088).有bcl-6基因重排的DLBCL中,24例(24/33,72.7%)cyclin D3呈现高水平表达,明显高于bcl-6基因无易位DLBCL组中的cyclin D3表达(37/81,45.7%,P=0.009).在33例bcl-6基因易位的DLBCL中,29例(87.9%)为Ann Arbor Ⅲ-Ⅳ期,较bcl-6基因无易位高者(65/85,76.5%,P=0.167).单变量Cox风险比模型分析发现,bcl-6基因重排与患者的生存率呈负相关,是一个危险因子,相对危险度(RR)为1.842.结论 bcl-6基因重排导致的bcl-6蛋白表达上调参与了部分DLBCL的发病过程,并可能成为DLBCL的ABC样亚型的一个分子标志.

Clinicopathologic significance of bel-6 gene rearrangement and expression in three molecular subgroups of diffuse large B-cell lymphoma

Objective To investigate the role of bcl-6 gene rearrangement and bcl-6 expression in three molecular subgroups of diffuse large B-cell lymphoma(DLBCL)and its elinicopathological significance.Methods Tissue microarray including 163 newly diagnosed DLBCL was constructed.Fluorescence in situ hybridization(FISH)was performed to detect the bcl-6 gene rearrangement and immunohistochemistry(EnVision method)was used to evaluate the expression of bcl-6,Ki-67,cyclin D3,Geminin and P27Kipl proteins in DLBCL.The association with clinicopathological features was analyzed.Results One hundred and forty nine of 163 cases were further classified into three molecular subgroups:40 cases of germinal center B-cell-like(GCB)type,75 cases of activated non-germinal center B-cell-like (ABC)type,34 cases of Type 3.Of these 149 cases,FISH for bcl-6 gene rearrangement was successful in 118 cases.bcl-6 gene rearrangement was observed in 33 of 118(28.0%)cases.The bcl-6 gene rearrangement was more frequently seen in me ABC subgroup(22/62,35.5%)than in GCB(6/31,19.4%)and Type 3 subgroups(5/25,20.0%,P=0.16).The correlation of bcl-6 gene rearrangement and expression of its encoded protein was further analyzed.Most of DLBCL(26/33,78.8%)with bcl-6 gene rearrangement presented with overexpression of its encoded protein,which was higher than those without bcl-6 gene rearrangement(53/84,62.4%,P=0.088).DLBCL with bcl-6 gene rearrangement(24/33.72.7%)more frequently expressed cyclin D3,and had a higher proliferative activity than those without bcl-6 gene rearrangement(37/81,45.7%,P=0.009).Twenty-nine of 33(87.9%)cages of DLBCL with bcl-6 gene rearrangement presented with advanced stage(Ann Arbor stage Ⅲ/Ⅳ),which was hisher than those without bcl-6 gene rearrangement(65/85,76.5%,P=0.167).Univariate Cox proportional hazards regression analysis showed that bcl-6 gene rearrangement was associated with an increased relative risk (at 1.842)of death in DLBCL cases compared with those without bcl-6 gene rearrangement.Conclusion Overexpression of bcl-6 protein caused by bcl-6 gene rearrangement may play some important roles in the devdopment and/or progression of a subset of DLBCL.