MYC/BCL2 Protein Co-Expression Defines a Unique Subset of Aggressive B-Cell Lymphomas and Contributes to the Inferior Prognosis of Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program Study
Shimin Hu, Alexander Tzankov, Carlo Visco, Attilio Orazi, Govind Bhagat, Eric D Hsi, Maurilio Ponzoni, Miguel A Piris, Michael B Moller, L Jeffrey Medeiros, Ken H Young. University of Texas MD Anderson Cancer Center, Houston, TX
Background: Diffuse large B-cell lymphoma (DLBCL) is stratified into two prognostic groups according to gene expression signatures, with the germinal center B-cell (GCB) subtype being favorable and the activated B-cell (ABC)-like subtype being unfavorable. ABC-DLBCL is characterized by its constitutive NF-kB activation and upregulation of many downstream genes. However, it is not known which proteins contribute to the poor prognosis of ABC-DLBCL.
Design: 466 patients with de novo DLBCL treated with R-CHOP chemotherapy were studied for MYC and BCL2 protein expression as assessed by immunohistochemistry. The results were correlated with clinicopathologic features, cell-of-origin subtypes, molecular genetic changes, gene expression profiles (GEP), and clinical outcome.
Results: Approximately 34% of DLBCL demonstrated MYC/BCL2 co-expression. Patients with MYC+BCL2+ DLBCL had markedly worse overall survival (OS, p<0.0001) and progression-free survival (PFS, p<0.0001) compared with patients without MYC/BCL2 co-expression. However, neither MYC nor BCL2 protein expression alone predicted prognosis. MYC/BCL2 co-expression was more common in the ABC subtype (46% ABC vs 22% GCB, p<0.0001). After excluding tumors with MYC/BCL2 co-rearrangement, known to be more common in GCB subtype, 47% ABC vs 17% GCB DLBCL showed MYC/BCL2 co-expression (p<0.0001). Patients with ABC-DLBCL vs GCB-DLBCL showed similar OS and PFS in the absence of MYC/BCL2 co-expression. Similarly, in patients with MYC+BCL2+ DLBCL, cell-of-origin did not correlate with prognosis. GEP studies revealed a striking stroma-poor gene expression signature in MYC+BCL2+ DLBCL. GCB and ABC subtypes of MYC+BCL2+ DLBCL demonstrated differentially expressed gene profiles largely similar to those of GCB and ABC subtypes published previously. However, few genes were differentially expressed between GCB and ABC-DLBCLs in the absence of MYC+BCL2+ co-expression.
Conclusions: Unlike DLBCL with MYC/BCL2 co-rearrangement that are usually of GCB subtype, DLBCL with MYC+BCL2+ co-expression are more often of ABC subtype. The high frequency and adverse impact of MYC/BCL2 co-expression may explain the poorer prognosis of patients with ABC-DLBCL. MYC/BCL2 co-expression assessed by immunohistochemistry provides a cost-effective approach to stratify patients with DLBCL.
Monday, March 4, 2013 1:00 PM
Proffered Papers: Section C, Monday Afternoon