BackgroundDespite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL.MethodsWe analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients.ResultsWe identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis.ConclusionCOMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.Trial RegistrationClinicalTrials.gov NCT01502982
Abstract. rituximab, a cD20-specific antibody, is used with chemotherapy as a treatment for diffuse large B cell lymphoma (DLBCL). Although many patients benefit from the addition of rituximab to chemotherapy, a favourable response is not achieved in approximately 30% of cases. this sets a prerequisite to better understand the response and resistance mechanisms of rituximab. to do so, we analyzed the gene expression profiles of one rituximab unresponsive and two responsive DlBcl cell lines. In the responsive cells, rituximab affected the expression of genes related to apoptosis, lymphocyte signaling and cytokine response. our data show rituximab-response to be associated with gene expression in classical signaling cascades involved in cell growth and differentiation, such as previously identified MAPK and completely novel Wnt and tgF-β pathways. Furthermore, our findings support earlier observations that rituximab can induce direct apoptosis and suggest the cell of origin to be associated with the cellular outcome. After validation of cellular results, we used a cohort of 233 r-cHop treated DlBcl patients and found several of the most differentiating genes to have impact on survival. together, the results provide an advanced picture of the cD20 mediated signaling of DlBcl cells and may provide new targets in future treatment protocols.
Development of targeted agents for the treatment of diffuse large B-cell lymphoma includes clinical evaluation of enzastaurin, an agent that suppresses signaling through protein kinase C-b and AKT pathways. To determine whether protein kinase C-b expression has prognostic significance for diffuse large B-cell lymphoma patients treated with immunochemotherapy, we analyzed the expression of protein kinase C-b II, BCL-2 and cell of origin immunohistochemically from pretreatment samples of 95 diffuse large B-cell lymphoma patients. All patients received rituximab with CHOP or CHOEP. According to Kaplan-Meier analyses, overall survival at 3 years was better among the patients with low than high protein kinase C-b II protein levels (94 vs 76%, P ¼ 0.036). The prognostic value of protein kinase C-b II expression on survival was seen in the patients with low and high International Prognostic Index risk groups, and in all molecular entities. Gene expression data from an independent set of 233 diffuse large B-cell lymphoma patients treated with a combination of rituximab and CHOP-like chemotherapy was analyzed in comparison. Accordingly, a better 3-year overall survival was observed among the subgroup with low protein kinase C-b II mRNA levels (84 vs 68%, P ¼ 0.005). In multivariate analysis with cell of origin, protein kinase C-b II mRNA expression remained as an independent predictor for overall survival. Together, the data show that protein kinase C-b II expression has prognostic significance in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Modern Pathology (2010) 23, 686-693; doi:10.1038/modpathol.2010 published online 26 February 2010 Keywords: diffuse large B-cell lymphoma; R-CHOP; protein kinase C-b II; prognosis Diffuse large B-cell lymphoma is the most common lymphoma subtype comprising 30-40% of all nonHodgkin lymphomas. It is an aggressive disease, of which only 50% of the patients can be cured with anthracyclin-based chemotherapy. However, the concurrent administration of CD20 antibody, rituximab, with different chemotherapies has resulted in a significant improvement of survival compared to chemotherapy alone.
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