Double-hit Signature with <i>TP53</i> Abnormalities Predicts Poor Survival in Patients with Germinal Center Type Diffuse Large B-cell Lymphoma Treated with R-CHOP
Joo Y. Song, Anamarija M. Perry, Alex F. Herrera, Lu Chen, Pamela Skrabek, Michel R. Nasr, Rebecca A. Ottesen, Janet Nikowitz, Victoria Bedell, Joyce Murata‐Collins, Yuping Li, Christine McCarthy, Raju Pillai, Jinhui Wang, Xiwei Wu, Jasmine Zain, Leslie Popplewell, Larry W. Kwak, Auayporn Nademanee, Joyce C. Niland, David W. Scott, Qiang Gong, Wing C. Chan, Dennis D. Weisenburger
Abstract
Abstract Purpose: We performed detailed genomic analysis on 87 cases of de novo diffuse large B-cell lymphoma of germinal center type (GCB DLBCL) to identify characteristics that are associated with survival in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Experimental Design: The cases were extensively characterized by combining the results of IHC, cell-of-origin gene expression profiling (GEP; NanoString), double-hit GEP (DLBCL90), FISH cytogenetic analysis for double/triple-hit lymphoma, copy-number analysis, and targeted deep sequencing using a custom mutation panel of 334 genes. Results: We identified four distinct biologic subgroups with different survivals, and with similarities to the genomic classifications from two large retrospective studies of DLBCL. Patients with the double-hit signature, but no abnormalities of TP53, and those lacking EZH2 mutation and/or BCL2 translocation, had an excellent prognosis. However, patients with an EZB-like profile had an intermediate prognosis, whereas those with TP53 inactivation combined with the double-hit signature had an extremely poor prognosis. This latter finding was validated using two independent cohorts. Conclusions: We propose a practical schema to use genomic variables to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies.