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

Nathalie A. Johnson, 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 Braziel & 11 others 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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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.

Original languageEnglish (US)
Pages (from-to)3452-3459
Number of pages8
JournalJournal of Clinical Oncology
Volume30
Issue number28
DOIs
StatePublished - Oct 1 2012

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Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Doxorubicin
Cyclophosphamide
Proto-Oncogene Proteins c-bcl-2
Proteins
Immunohistochemistry
Messenger RNA
Survival
Rituximab
Disease-Free Survival
B-Lymphocytes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Johnson, Nathalie A.; Slack, Graham W.; Savage, Kerry J.; Connors, Joseph M.; Ben-Neriah, Susana; Rogic, Sanja; Scott, David W.; Tan, King L.; Steidl, Christian; Sehn, Laurie H.; Chan, Wing C.; Iqbal, Javeed; Meyer, Paul N.; Lenz, Georg; Wright, George; Rimsza, Lisa M.; Valentino, Carlo; Brunhoeber, Patrick; Grogan, Thomas M.; Braziel, Rita; Cook, James R.; Tubbs, Raymond R.; Weisenburger, Dennis D.; Campo, Elias; Rosenwald, Andreas; Ott, German; Delabie, Jan; Holcroft, Christina; Jaffe, Elaine S.; Staudt, Louis M.; Gascoyne, Randy D.

In: Journal of Clinical Oncology, Vol. 30, No. 28, 01.10.2012, p. 3452-3459.

Research output: Contribution to journalArticle

Johnson, NA, Slack, GW, Savage, KJ, Connors, JM, Ben-Neriah, S, Rogic, S, Scott, DW, Tan, KL, Steidl, C, Sehn, LH, Chan, WC, Iqbal, J, Meyer, PN, Lenz, G, Wright, G, Rimsza, LM, Valentino, C, Brunhoeber, P, Grogan, TM, Braziel, R, Cook, JR, Tubbs, RR, Weisenburger, DD, Campo, E, Rosenwald, A, Ott, G, Delabie, J, Holcroft, C, Jaffe, ES, Staudt, LM & Gascoyne, RD 2012, 'Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone', Journal of Clinical Oncology, vol. 30, no. 28, pp. 3452-3459. https://doi.org/10.1200/JCO.2011.41.0985
Johnson, Nathalie A. ; Slack, Graham W. ; Savage, Kerry J. ; Connors, Joseph M. ; Ben-Neriah, Susana ; Rogic, Sanja ; Scott, David W. ; Tan, King L. ; Steidl, Christian ; Sehn, Laurie H. ; Chan, Wing C. ; Iqbal, Javeed ; Meyer, Paul N. ; Lenz, Georg ; Wright, George ; Rimsza, Lisa M. ; Valentino, Carlo ; Brunhoeber, Patrick ; Grogan, Thomas M. ; Braziel, Rita ; Cook, James R. ; Tubbs, Raymond R. ; Weisenburger, Dennis D. ; Campo, Elias ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Holcroft, Christina ; Jaffe, Elaine S. ; Staudt, Louis M. ; Gascoyne, Randy D. / Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 28. pp. 3452-3459.
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title = "Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone",
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.",
author = "Johnson, {Nathalie A.} and Slack, {Graham W.} and Savage, {Kerry J.} and Connors, {Joseph M.} and Susana Ben-Neriah and Sanja Rogic and Scott, {David W.} and Tan, {King L.} and Christian Steidl and Sehn, {Laurie H.} and Chan, {Wing C.} and Javeed Iqbal and Meyer, {Paul N.} and Georg Lenz and George Wright and Rimsza, {Lisa M.} and Carlo Valentino and Patrick Brunhoeber and Grogan, {Thomas M.} and Rita Braziel and Cook, {James R.} and Tubbs, {Raymond R.} and Weisenburger, {Dennis D.} and Elias Campo and Andreas Rosenwald and German Ott and Jan Delabie and Christina Holcroft and Jaffe, {Elaine S.} and Staudt, {Louis M.} and Gascoyne, {Randy D.}",
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TY - JOUR

T1 - Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

AU - Johnson, Nathalie A.

AU - Slack, Graham W.

AU - Savage, Kerry J.

AU - Connors, Joseph M.

AU - Ben-Neriah, Susana

AU - Rogic, Sanja

AU - Scott, David W.

AU - Tan, King L.

AU - Steidl, Christian

AU - Sehn, Laurie H.

AU - Chan, Wing C.

AU - Iqbal, Javeed

AU - Meyer, Paul N.

AU - Lenz, Georg

AU - Wright, George

AU - Rimsza, Lisa M.

AU - Valentino, Carlo

AU - Brunhoeber, Patrick

AU - Grogan, Thomas M.

AU - Braziel, Rita

AU - Cook, James R.

AU - Tubbs, Raymond R.

AU - Weisenburger, Dennis D.

AU - Campo, Elias

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Holcroft, Christina

AU - Jaffe, Elaine S.

AU - Staudt, Louis M.

AU - Gascoyne, Randy D.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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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U2 - 10.1200/JCO.2011.41.0985

DO - 10.1200/JCO.2011.41.0985

M3 - Article

VL - 30

SP - 3452

EP - 3459

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 28

ER -