MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program

Abstract

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

Figure 1

Prognostic impact of MYC/BCL2 coexpression in DLBCL. (A-B) OS (A) and PFS (B) of patients with DLBCL with MYC/BCL2 coexpression (MYC⁺BCL2⁺) in the training set. (C-D) OS of patients with MYC⁺ DLBCL in the presence (C) or absence (D) of BCL2 coexpression in the training set. (E-F) OS of patients with BCL2⁺ DLBCL in the presence (E) or absence (F) of MYC coexpression in the training set.

Figure 2

Prognostic impact of MYC/BCL2 coexpression in DLBCL risk-stratified according to clinicopathologic parameters. (A-B) OS (A) and PFS (B) of patients with MYC⁺BCL2⁺ DLBCL of the GCB subtype in the training set. (C-D) OS (C) and PFS (D) of patients with MYC⁺BCL2⁺ DLBCL of the ABC subtype in the training set. (E-F) OS (E) and PFS (F) of patients with MYC⁺BCL2⁺ DLBCL risk-stratified according to IPI risk scores in the training set. DP, MYC/BCL2 double-positive; Non-DP, non–double positive.

Figure 3

Frequency of BCL2 and MYC expression in COO subtypes of DLBCL. (A) Relative frequency of the ABC vs GCB subtype in DLBCL positive for BCL2 expression, MYC expression, or MYC/BCL2 coexpression in the training set. (B) Frequency of BCL2 expression, MYC expression, or MYC/BCL2 coexpression (in the presence or absence of MYC/BCL2 corearrangements, DH) in DLBCL of the ABC and GCB subtypes in the training set. DH, double hit.

Figure 4

MYC/BCL2 coexpression contributes to the inferior prognosis of ABC-DLBCL. (A-B) OS (A) and PFS (B) of the ABC vs GCB subtype of DLBCL in the entire training set. COO classification of 411 cases was based on GEP results and 55 cases based on IHC results. (C-D) OS (C) and PFS (D) of the ABC vs GCB subtype of DLBCL after all MYC⁺BCL2⁺ cases were excluded. (E-F) OS (E) and PFS (F) of the ABC vs GCB subtype in MYC⁺BCL2⁺ DLBCL.

Figure 5

Prognostic impact of MYC/BCL2 coexpression in DLBCL is independent of MYC/BCL2 corearrangement and TP53 mutation status. (A-B) OS (A) and PFS (B) of patients with MYC/BCL2 double-hit DLBCL. (C-D) OS (C) and PFS (D) of patients with MYC⁺BCL2⁺ DLBCL in the absence of MYC/BCL2 double hit. (E) OS of patients with MYC⁺BCL2⁺ DLBCL in the absence of TP53 mutation. (F) Prognostic impact of TP53 mutation in MYC⁺BCL2⁺ DLBCL.

Figure 6

MYC/BCL2 coexpression contributes to the different gene expression profiles between GCB and ABC subtypes of DLBCL. (A) GEP comparison between the ABC vs GCB subtype of DLBCL with MYC/BCL2 coexpression. Of 157 cases of MYC⁺BCL2⁺ DLBCL, GEP was successfully performed in 149 cases (ABC: 102; GCB: 47). DP, MYC/BCL2 double positive. A total of 208 genes corresponding to 365 probe sets were differentially expressed (P < .001). (B) GEP comparison between the ABC (30 cases) vs GCB (58 cases) subtype of DLBCL negative for both MYC and BCL2 protein expression. A total of 20 genes corresponding to 30 probesets were differentially expressed between the 2 COO subtypes (P < .01). DN, MYC/BCL2 double negative.

Figure 7

Gene expression signature of DLBCL with MYC/BCL2 coexpression. Comparison of GEPs of DLBCL with MYC/BCL2 coexpression (149 cases) vs DLBCL negative for MYC and BCL2 expression (88 cases). A total of 153 genes corresponding to 219 probe sets were differentially expressed (P < .001).