弥漫性大B细胞淋巴瘤患者组织中CXCL9、CXCR3表达与临床病理特征及预后的关系

The relationship between the expression of CXCL9 and CXCR3 and clinicopathological characteristics and prognosis in the tissues of patients with diffuse large B-cell lymphoma

目的探究弥漫性大B细胞淋巴瘤(DLBCL)患者组织中趋化因子9(CXCL9)及其受体CXCR3的表达水平与临床病理特征及预后的关系。方法收集2015年1月~2016年1月在我院采用R-CHOP化疗方案治疗的92例DLBCL患者,均通过淋巴结活检获取DLBCL肿瘤组织标本,及50例病灶旁正常淋巴组织标本。利用癌症基因组图谱(TCGA)数据库分析CXCL9、CXCR3基因在DLBCL肿瘤组织和正常淋巴组织中的表达情况,并利用免疫组化分析CXCL9、CXCR3蛋白在DLBCL肿瘤组织和正常淋巴组织中的阳性表达情况;分析CXCL9、CXCR3蛋白表达水平与临床病理特征及预后的关系。采用Kaplan-Meier法分析CXCL9、CXCR3蛋白表达水平与DLBCL复发的关系,采用COX回归分析影响DLBCL患者复发的危险因素。结果TCGA数据库中CXCL9、CXCR3基因在DLBCL肿瘤组织中表达水平与正常淋巴组织比较差异有统计学意义(P<0.05)。CXCL9、CXCR3蛋白在DLBCL肿瘤组织中的阳性表达率明显高于正常组织(P<0.05)。DLBCL肿瘤组织中CXCL9与CXCR3蛋白表达呈正相关(χ^(2)=15.836,P<0.001);CXCL9、CXCR3蛋白表达水平与DLBCL患者年龄、性别、原发部位、乳酸脱氢酶水平、国际预后指数(IPI)评分无关(P>0.05),与Ann Arbor分期、组织学分型、Ki67阳性率有关(P<0.05)。DLBCL患者肿瘤组织CXCL9高表达组5年累积复发率高于低表达组,差异有统计学意义(χ^(2)=9.788,P<0.001);CXCR3高表达组5年累积复发率高于低表达组,差异有统计学意义(χ^(2)=17.610,P<0.001)。多因素COX分析结果显示,CXCL9高表达、CXCR3高表达、Ann Arbor分期Ⅲ~Ⅳ期、非生发中心型是影响DLBCL患者复发的独立危险因素(均P<0.05)。结论DLBCL患者肿瘤组织中CXCL9、CXCR3表达上调,其表达水平与患者Ann Arbor分期、组织学分型有关,可能是DLBCL患者预后的潜在靶标。

Objective To explore the relationship between the expression levels of chemokine 9(CXCL9)and its receptor CXCR3 in the tissues of patients with diffuse large B-cell lymphoma(DLBCL)and clinicopathological characteristics and prognosis.Methods From January 2015 to January 2016,92 patients with DLBCL treated with R-CHOP chemotherapy in our hospital were collected,and DLBCL tumor tissue samples and 50 normal lymph tissue samples near the focus were obtained through lymph node biopsy.The expression of CXCL9 and CXCR3 genes in DLBCL tumor tissues and normal lymphoid tissues was analyzed by cancer genome atlas(TCGA)database,and the positive expression of CXCL9 and CXCR3 protein in DLBCL tumor tissue and normal lymphoid tissue was analyzed by immunohistochemistry,and the relationship between CXCL9 and CXCR3 protein expression levels and clinicopathological characteristics and prognosis was analyzed.Kaplan-Meier method was used to analyze the relationship between the expression levels of CXCL9 and CXCR3 protein and the recurrence of DLBCL.COX regression was used to analyze the risk factors of recurrence in patients with DLBCL.Results The expression levels of CXCL9 and CXCR3 genes in DLBCL tumor tissues in the TCGA database were significantly different from those in normal lymphoid tissues(P<0.05);the positive expression rates of CXCL9 and CXCR3 proteins in DLBCL tumor tissues were significantly higher than their positive expression rates in normal tissues(P<0.05);there was a positive correlation between CXCL9 and CXCR3 proteins expression in DLBCL tumor tissue(χ^(2)=15.836,P<0.001);the expression levels of CXCL9 and CXCR3 protein were not related to the age,gender,primary site,lactate dehydrogenase level,and international prognostic index(IPI)score of DLBCL patients(P>0.05),but were related to Ann Arbor stage,histological type and Ki67 positive rate(P<0.05);the 5-year cumulative recurrence rate of DLBCL patients in CXCL9 high expression group was 68.52%,which was significantly higher than 37.50% of patients in low expression group,and the difference was statistically significant(χ^(2)=9.788,P<0.001);the 5-year cumulative recurrence rate of CXCR3 high expression group was 73.68%,which was significantly higher than 28.57% of low expression group,and the difference was statistically significant(χ^(2)=17.610,P<0.001);the results of multivariate COX analysis showed that high expression of CXCL9,high expression of CXCR3,Ann Arbor stagesⅢtoⅣand non germinal center were independent risk factors for recurrence in DLBCL patients(all P<0.05).Conclusion The expressions of CXCL9 and CXCR3 in tumor tissues of DLBCL patients are up-regulated,and their expression levels are related to the Ann Arbor stage and histological type of patients,which may be potential targets indicating the prognosis of DLBCL patients.