Patterns of IgH rearrangement stratify prognosis of diffuse large B-cell lymphoma, which could be associated with CDC25A

Over 80% of patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP achieve complete remission with variable 5-year overall survival (OS) rates of 60 to 70% depending on the preexisting risk factors. We herein attempted to stratify DLBCL by the patterns of immunoglobulin heavy chain gene rearrangement (IgH-R) by using a PCR-based clonality detection method to predict prognosis of the patients with DLBCL. We retrospectively analyzed 81 patients with DLBCL who were treated at our hospital from 2006 to 2013 and had data on IgH-R of lymphoma cells at diagnosis. IgH-R analyses identified a uniform pattern of IgH-R harboring all frame regions (FR)1-3 not completely involving DH1-7 in 15 out of 26 patients, who failed to obtain complete remission (CR). Moreover, CR rate was quite low ((7/22 (32%)) in these patients with this IgH-R pattern. We evaluated prognostic parameters of these patients with special reference to patterns of IgH-R by univariate and multivariate proportional-hazard model. Multivariate analysis revealed that IgH-R in all FR1-3 without entire DH1-7 was significantly associated with adverse overall survival. Then, gene expression profiling of mRNA elicited the candidate genes associated with poorer prognosis stratified by IgH-R patterns. Among them, CDC25A mRNA was significantly amplified by real-time PCR and then further analysis of its protein with immunostaining confirmed that CDC25A could be a responsible gene for prognosis of patients with DLBCL. These results may shed light on individualized therapeutic modalities by the stratification of patients in accordance with patterns of IgH-R. Statistical analyses suggested that IgH-R in all FR1-3 regions in conjunction with no IgH-R in DH1-7 is associated with significant adverse impact on prognosis of the patients with DLBCL. Next, we conducted gene expression profiling test of mRNA between consecutive IgH-R in FR1-3 and the other patterns to identify responsible genes associated with poor prognosis. 3 samples showing IgH-R in entire FR1-3 but not DH1-7 and 3 samples bearing no IgH-R in all FR1-3 were selected for gene expression profiling of mRNA.