Myc~+和Bcl-2~+Myc~+年轻DLBCL患者中Bcl-6的表达及其临床意义
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摘要
目的:探讨初治、年轻的弥漫大B细胞淋巴瘤(di use large B cell lymphoma,DLBCL)患者中Bcl-6的表达情况,并进一步分析Bcl-6表达在Myc阳性表达(Myc~+)以及Bcl-2和Myc阳性共表达(Bcl-2~+Myc~+)的年轻DLBCL患者中的临床意义。方法:采用免疫组织化学法检测116例初治、年轻DLBCL患者肿瘤组织中Bcl-6、Myc和Bcl-2蛋白的表达水平,并收集完整的患者临床和病理资料,回顾性分析Bcl-6表达与Myc~+和Bcl-2~+Myc~+年轻DLBCL患者预后的相关性。结果:单一Bcl-6蛋白表达与年轻DLBCL患者的预后无相关性(P> 0.05);但当伴有Myc~+表达时,Bcl-6阴性表达(Bcl-6-)患者的预后明显比Bcl-6阳性表达(Bcl-6~+)患者差(P <0.05)。多因素分析发现,Bcl-6-Myc~+是独立于国际预后指数(international prognostic index,IPI)的显著不良预后因素(P <0.05),同时Bcl-6-Bcl-2~+Myc~+患者的预后与Bcl-6~+Bcl-2~+Myc~+患者相比显著较差(P <0.05)。结论:Bcl-6-表达可增加Myc~+和Bcl-2~+Myc~+年轻DLBCL患者的不良预后风险。
Objective:To investigate the expression of Bcl-6 in newly diagnosed and young patients with diffuse large B cell lymphoma(DLBCL), and to further explore its clinical significance in young DLBCL patients with Myc positive expression (Myc~+) or Bcl-2 and Myc positiveexpressions(Bcl-2~+Myc~+).Methods:Immunohistochemical(IHC) staining was used to detect the expressions of Bcl-6, Myc and Bcl-2 in 116 newly diagnosed and young patients with DLBCL, and the complete clinical and pathological data were collected. The relationship between the expression levels of Bcl-6 protein and the prognosis of young DLBCL patients with Myc~+ and Bcl-2~+Myc~+ was retrospectively analyzed. Results:There was no significantly correlation between the expression of Bcl-6 alone and the prognosis of young DLBCL patients(P > 0.05). However, for the DLBCL patients with Myc~+, the prognosis in Bcl-6 negative(Bcl-6-) group was worse than that in Bcl-6 positive(Bcl-6~+) group(P < 0.05). Furthermore, the multivariate COX regression analysis showed that Bcl-6-Myc~+ expression was a significant independent factor of adverse prognosis except for the international prognostic index(IPI)(P < 0.05). Meanwhile, the prognosis of DLBLC patients with Bcl-6-Bcl-2~+Myc~+ was significantly worse than that of the patients with Bcl-6~+Bcl-2~+Myc~+(P < 0.05). Conclusion:Bcl-6 negative expression can increase the risk of poor prognosis in young DLBCL patients with Myc~+ or Bcl-2~+Myc~+.
Objective:To investigate the expression of Bcl-6 in newly diagnosed and young patients with diffuse large B cell lymphoma(DLBCL), and to further explore its clinical significance in young DLBCL patients with Myc positive expression (Myc~+) or Bcl-2 and Myc positiveexpressions(Bcl-2~+Myc~+).Methods:Immunohistochemical(IHC) staining was used to detect the expressions of Bcl-6, Myc and Bcl-2 in 116 newly diagnosed and young patients with DLBCL, and the complete clinical and pathological data were collected. The relationship between the expression levels of Bcl-6 protein and the prognosis of young DLBCL patients with Myc~+ and Bcl-2~+Myc~+ was retrospectively analyzed. Results:There was no significantly correlation between the expression of Bcl-6 alone and the prognosis of young DLBCL patients(P > 0.05). However, for the DLBCL patients with Myc~+, the prognosis in Bcl-6 negative(Bcl-6-) group was worse than that in Bcl-6 positive(Bcl-6~+) group(P < 0.05). Furthermore, the multivariate COX regression analysis showed that Bcl-6-Myc~+ expression was a significant independent factor of adverse prognosis except for the international prognostic index(IPI)(P < 0.05). Meanwhile, the prognosis of DLBLC patients with Bcl-6-Bcl-2~+Myc~+ was significantly worse than that of the patients with Bcl-6~+Bcl-2~+Myc~+(P < 0.05). Conclusion:Bcl-6 negative expression can increase the risk of poor prognosis in young DLBCL patients with Myc~+ or Bcl-2~+Myc~+.
引文
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[3]CHEN PM,YANG MH,YU IT,et al.Low incidence of BCL-6 gene alterations for diffuse large B-cell lymphomas in Taiwan Chinese[J].Cancer,2002,94(10):2635-2644.
[4]SHIOZAWA E,YAMOCHI-ONIZUKA T,TAKIMOTO M,et al.The GCB subtype of diffuse large B-cell lymphoma is less frequent in Asian countries[J].Leuk Res,2007,31(11):1579-1583.
[5]KLUK MJ,CHAPUY B,SINHA P,et al.Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas[J].PLoS One,2012,7(4):e33813.
[6]PERRY AM,ALVARADO-BERNAL Y,LAURINI JA,et al.MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab[J].Br JHaematol,2014,165(3):382-391.
[7]ZHOU M,WANG J,OUYANG J,et al.MYC protein expression is associated with poor prognosis in diffuse large Bcell lymphoma patients treated with RCHOP chemotherapy[J].Tumour Biol,2014,35(7):6757-6762.
[8]WANG XJ,MEDEIROS LJ,BUESO-RAMOS CE,et al.P53 expression correlates with poorer survival and augments the negative prognostic effect of MYCrearrangement,expression or concurrent MYC/BCL2 expression in diffuse large B-cell lymphoma[J].Mod Pathol,2017,30(2):194-203.
[9]VEELKEN H,VIK DANNHEIM S,SCHULTEMOENTING J,et al.Immunophenotype as prognostic factor for diffuse large B-cell lymphoma in patients undergoing clinical risk-adapted therapy[J].Ann Oncol,2007,18(5):931-939.
[10]HORN H,ZIEPERT M,BECHER C,et al.MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma[J].Blood,2013,121(12):2253-2263.
[11]KAWAMOTO K,MIYOSHI H,YOSHIDA N,et al.MYC translocation and/or BCL2 protein expression are associated with poor prognosis in diffuse large B-cell lymphoma[J].Cancer Sci,2016,107(6):853-861.
[12]CATTORETTI G,PASQUALUCCI L,BALLON G,et al.Deregulated BCL6expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice[J].Cancer Cell,2005,7(5):445-455.
[13]PENNANEN M,HAGSTR?M J,HEISKA-NEN I,et al.C-myc expression in adrenocortical tumours[J].J Clin Pathol,2018,71(2):129-134.
[14]JOHNSON NA,SLACK GW,SAVAGE KJ,et al.Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone[J].J Clin Oncol,2012,30(28):3452-3459.
[15]GREEN TM,YOUNG KH,VISCO C,et al.Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone[J].J Clin Oncol,2012,30(28):3460-3467.
[16]YE BH,LISTA F,LO COCO F,et al.Alterations of a zinc finger-encoding gene,BCL-6,in diffuse largecell lymphoma[J].Science,1993,262(5134):747-750.
[17]YE BH,CATTORETTI G,SHEN Q,et al.The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation[J].Nat Genet,1997,16(2):161-170.
[18]IQBAL J,GREINER TC,PATEL K,et al.Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma[J].Leukemia,2007,21(11):2332-2343.
[19]ROBERTS AW,DAVIDS MS,PAGEL JM,et al.Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia[J].N Engl J Med,2016,374(4):311-322.
[20]ZHOU Z,SEHN LH,RADEMAKER AW,et al.An enhanced International Prognostic Index(NCCN-IPI)for patients with diffuse large B-cell lymphoma treated in the rituximab era[J].Blood,2014,123(6):837-842.