The Study And Clinical Application Of MYC And BCL2 In Diffuse Large B Cell Lymphoma

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Expression and clinical significance of MYC protein in patients with diffuse large B cell lymphomaObjective:This study aims to detect the expression of MYC protein in diffuse large B cell lymphoma tissues and to investigate relationship with clinical pathological features and the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma patients.Methods:A total of sixty patients with DLBCL from from 2008 January to 2013 September in the Affiliated Drum Tower Hospital of Nanjing University Medical School were included.All cases were confirmed as diffuse large B cell lymphoma by pathological biopsy.Formalin-fixed paraffin-embedded(FFPE)DLBCL samples were analyzed for MYC protein expression.IHC was used to evaluate the MYC protein expression and the international prognostic variables.Results:1.The high MYC protein expression was shown in 21 patients(35.0%).2.Patients in non-GCB subgroup tended to have a higher incidence of MYC protein expression than that in GCB subgroup(43%vs.13%,P=0.028).3.According to univariate analysis that high MYC protein expression and high IPI are poor prognosis factors(P<0.05).4.According to multivariate analysis,it observed a significant prognostic value of MYC protein expression for OS(P= 0.021)and PFS(P=0.040)was observed.However,low IPI score was an independent factor of not PFS(P=0.091)but only better OS(P= 0.045).5.The new prognostic model was able to distinguish patients with different 3-year OS(P<0.001)and 3-year estimated PFS(P<0.001).Conclusions:1.MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL2.The combinative model with IPI score and MYC protein expression could stratify high risk DLBCL,and provide a theoretical basis for making clinical decision.Part ? The study of MYC and BCL2 in diffuse large B cell lymphomaObjective:Diffuse large B-cell lymphoma(DLBCL)is the most commonly seen non-Hodgkin'S lymphoma(NHL).On the basis of chemotherapy and immunotherapy,some patients have a good prognosis,but still a considerable number of patients suffer a strongly aggressive DLBCL with poor treatment effects.Since the overall prognosis presents considerable heterogeneity,more ideal prognostic indicators should be found for better risk stratification.Recently,MYC/BCL2 protein co-expression has attracted more attention.In this paper,MYC/BCL2 co-expression and the clinical features of DLBCL and its relationship with prognosis are studied,in the hope of exploring the significance of MYC/BCL2 co-expression in DLBCL.Methods:60 confirmed DLBCL cases were collected,which were equipped with complete clinical data and available paraffin—embedded tissues samples and admitted in the Affiliated Drum Tower Hospital of Nanjing University Medical School between 2008 January and 2013 September.Immunohistochemical examinations of MYC and BCL2 protein expression were carded out.In addition,this paper made a statistical analysis of the relationship between MYC/1BCL2 protein co-expressionIn and the progression-free survival(PFS)or overall survival(OS).Seven risk factors at diagnosis were identified,and a maximum of 7 points were assigned to each patient.Four risk groups were created:low(0-1),low-intermediate(2-3),high-intermediate(4),and high(5-7).We built an biological markers adjusted IPI with the goal of improving risk stratification.Results:1.We found 16 cases with MYC and BCL-2 protein coexpression.2.29 csees have FISH results.3 cases(11.1%)were MYC translocation.1 case(3.5%)was BCL2 translocation and 5 cases(17.2%)were MYC gene amplification.There was no DHL detected.3.Comparing MYC/BCL2 co-expression group with non-co-expression group,the PFS(HR=2.31,95%CI= 1.19-4.49)decreased significantly,but not the OS(HR=1.32,95%CI=0.48-3.63).4.The new prognostic model was able to distinguish patients with different 4-year OS(P<0.0001)and 4-year estimated PFS(P<0.0001).Conclusion:1.MYC/BCL2 co-expression has a poorer prognosis than non-co-expression.2.MYC/BCL2 co-expression is an independent prognostic risk factor.3.No case with MYC and BCL2 genes rearrangement coexisted.It needs to be added in more cases to verify.4.The MYC and BCL2 adjusted IPI could stratify high risk DLBCL.Part ? The clinical characteristics and prognosis of high risk patients identified by MYC and BCL2 adjusted IPIObjective:To evaluate whether the MYC and BCL2 adjusted IPI improves the stratification of high-risk patients with diffuse large B-cell lymphoma.Method:Seven risk factors were identified at diagnosis,and a maximum of 7 points were assigned to each patient.The patients were classified according to four risk groups:low(0-1),low-intermediate(2-3),high-intermediate(4),and high(5-7).We retrospectively examined 20 high-risk cases from 2008 January and 2013 September at the Nanjing Drum Tower Hospital.Results:1.17 of 20(65%)evaluable cases overexpressed MYC.2.Eighteen of 20(90%)evaluable cases showed BCL-2 overexpression.3.12 out of 20 cases(60%)demonstrated co-expression of MYC and BCL-2 proteins.4.The median follow-up was 36 months,OS and PFS of high risk patients were 33.3%± 16.1%and 16.9%± 13.5%,respectively.5.4 out of 20 cases were identified as low-intermediate risk according to the NCCN-IPI criteria.Conclusion:1.More high risk patiets have MYC/BCL2 co-expression.2.The MYC and BCL2 adjusted IPI could identify a subset of DLBCL patients with high-risk clinicopathological characteristics and poor clinical outcome.Part ? The clinical application of MYC and BCL2 adjusted IPI in the prognostic model of p65Objective:We estimated the expression of p65 in non-germinal center B-cell-like subtype diffuse large B-cell lymphoma,to investigate its relationship to clinicopathological features,and to clarify further evaluate its prognostic value and further evaluate impact of MYC and BCL2 adjusted IPI on the p65 prognostic model.Methods:The expression of the NF-?B/p65 protein was deteremined by immunohistochemistry in 49 non-GCB DLBCL.Survival was assessed by the Kaplan-Meier method and Cox multivariate analysis.According to the IPI adjusted by MYC and BCL2 adjusted IPI,the risk stratification analysis was conducted.The median patient follow-up period was 24 months.Results:1.14(28.6%)had positive p65 expression.2.The negative p65 group had significantly better survival compared to the positive p65 group in terms of both the 3-year estimated OS(91.2%vs.39.3%,p = 0.003)and PFS(75.6%vs.26.5%,p = 0.002).3.In patients with 4 or more risk factors(MYC and BCL2 adjusted IPI),p65 was an independent prognostic factor of OS(HR= 5.99,95%CI=1.39-25.75,P=0.016)and PFS(HR =4.01,95%CI=1.15-14.00,P=0.029).Conclusions1.p65 protein is a poor prognosis factor in non-GCB-DLBCL.2.The expression of p65 has independent prognostic value in high risk non-GCB DLBCL,and it is a suitable target for the development of new therapies.