Development and Validation of a Novel Four Gene-Pairs Signature for Predicting Prognosis in DLBCL Patients

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. Because individual clinical outcomes of DLBCL in response to standard therapy differ widely, new treatment strategies are being investigated to improve therapeutic efficacy. In this study, we identified a novel signature for stratification of DLBCL useful for prognosis prediction and treatment selection. First, 408 prognostic gene sets were selected from approximately 2500 DLBCL samples in public databases, from which four gene-pair signatures consisting of seven prognostic genes were identified by Cox regression analysis. Then, the risk score was calculated based on these gene-pairs and we validated the risk score as a prognostic predictor for DLBCL patient outcomes. This risk score demonstrated independent predictive performance even when combined with other clinical parameters and molecular subtypes. Evaluating external DLBCL cohorts, we demonstrated that the risk-scoring model based the four gene-pair signatures leads to stable predictive performance, compared with nine existing predictive models. Finally, high-risk DLBCL showed high resistance to DNA damage caused by anticancer drugs, suggesting that this characteristic is responsible for the unfavorable prognosis of high-risk DLBCL patients. These results provide a novel index for classifying the biological characteristics of DLBCL and clearly indicate the importance of genetic analyses in the treatment of DLBCL.