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. 2012 Oct 1;30(28):3452-9.
doi: 10.1200/JCO.2011.41.0985. Epub 2012 Jul 30.

Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

Nathalie A Johnson  1 , Graham W Slack, Kerry J Savage, Joseph M Connors, Susana Ben-Neriah, Sanja Rogic, David W Scott, King L Tan, Christian Steidl, Laurie H Sehn, Wing C Chan, Javeed Iqbal, Paul N Meyer, Georg Lenz, George Wright, Lisa M Rimsza, Carlo Valentino, Patrick Brunhoeber, Thomas M Grogan, Rita M Braziel, James R Cook, Raymond R Tubbs, Dennis D Weisenburger, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Christina Holcroft, Elaine S Jaffe, Louis M Staudt, Randy D Gascoyne
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Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

Nathalie A Johnson et al. J Clin Oncol. .

Abstract

Purpose: Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis.

Patients and methods: We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation.

Results: In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations.

Conclusion: Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Representative immunohistochemical analysis of MYC protein expression in diffuse large B-cell lymphoma (DLBCL). (A) Control: partial lymph node involvement by Burkitt's lymphoma (left) and follicular hyperplasia (right); there is bright nuclear staining of MYC protein in Burkitt's lymphoma cells, compared with < 5% of benign germinal center B cells stained for MYC (right). (B) MYC protein–positive DLBCL. (C) MYC protein–negative DLBCL.
Fig 2.
Fig 2.
Overall survival (OS) of patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone based on alterations in MYC and BCL2 in the training set. Kaplan-Meier curves represent OS according to (A) presence of MYC translocation (TR) and BCL2 protein expression (BCL2+), (B) presence of high MYC mRNA expression and BCL2 protein expression, and (C) presence of MYC and BCL2 protein expression. Log-rank P < .001 for both OS and progression-free survival. Total evaluable patients for the analyses: (A) n = 165, (B) n = 165, and (C) n = 164.
Fig 3.
Fig 3.
Overall (OS) and progression-free survival (PFS) of patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone according to presence of concurrent expression of MYC and BCL2 proteins (MYC+/BCL2+) and/or presence of concurrent MYC and BCL2 translocations. Kaplan-Meier curves represent OS according to presence of MYC+/BCL2+ in (A) the training cohort (n = 164) and (B) validation cohort (n = 140). (C) Both training and validation cohorts were combined because of the low frequency of double hits (DHITs). Patients were stratified according to presence of DHIT or MYC+/BCL2+ excluding DHITs. Four DHIT patient cases had no MYC protein expression; one had a missing value for BCL2 protein expression.
Fig A1.
Fig A1.
Distribution of MYC protein expression in diffuse large B-cell lymphoma (DLBCL) according to presence of MYC translocation. Blue bars represent the proportion of patients with DLBCL expressing MYC protein when MYC translocation is absent; gold bars represent the proportion expressing MYC protein when MYC translocation is present.
Fig A2.
Fig A2.
Age-related incidence of MYC and BCL2 deregulation in diffuse large B-cell lymphoma. ABC, activated B cell–like molecular subtype.
Fig A3.
Fig A3.
Overall survival (OS) of patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in the validation cohort based on presence of MYC and BCL2 protein expression. Log-rank P > .05 for both OS and progression-free survival.
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