Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries

Chi Young Ok; Ling Li; Zijun Y Xu-Monette; Carlo Visco; Alexander Tzankov; Ganiraju C Manyam; Santiago Montes-Moreno; Karen Dybkær; April Chiu; Attilio Orazi; Youli Zu; Govind Bhagat; Jiayu Chen; Kristy L Richards; Eric D Hsi; William W L Choi; J Han van Krieken; Jooryung Huh; Weiyun Ai; Maurilio Ponzoni; Andrés J M Ferreri; John P Farnen; Michael B Møller; Carlo E Bueso-Ramos; Roberto N Miranda; Jane N Winter; Miguel A Piris; L Jeffrey Medeiros; Ken H Young

doi:10.1158/1078-0432.CCR-13-3157

Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries

Chi Young Ok, Ling Li, Zijun Y Xu-Monette, Carlo Visco, Alexander Tzankov, Ganiraju C Manyam, Santiago Montes-Moreno, Karen Dybkær, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Jiayu Chen, Kristy L Richards, Eric D Hsi, William W L Choi, J Han van Krieken, Jooryung Huh, Weiyun Ai, Maurilio PonzoniAndrés J M Ferreri, John P Farnen, Michael B Møller, Carlo E Bueso-Ramos, Roberto N Miranda, Jane N Winter, Miguel A Piris, L Jeffrey Medeiros, Ken H Young

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Abstract

PURPOSE: Epstein-Barr virus-positive (EBV(+)) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV(+) DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).

RESULTS: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV(+) DLBCL from patients with EBV-negative (EBV(-)) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV(+) DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV(+) DLBCL versus EBV(-) DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV(+) DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.

CONCLUSIONS: The clinical characteristics of patients with EBV(+) versus EBV(-) DLBCL are similar and EBV infection does not predict a worse outcome. EBV(+) DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV(+) DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338-49. ©2014 AACR.

Original language	English
Journal	Clinical Cancer Research
Volume	20
Issue number	9
Pages (from-to)	2338-2349
Number of pages	12
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-13-3157
Publication status	Published - 1 May 2014

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Ok, C. Y., Li, L., Xu-Monette, Z. Y., Visco, C., Tzankov, A., Manyam, G. C., Montes-Moreno, S., Dybkær, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Chen, J., Richards, K. L., Hsi, E. D., Choi, W. W. L., van Krieken, J. H., Huh, J., Ai, W., ... Young, K. H. (2014). Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries. Clinical Cancer Research, 20(9), 2338-2349. https://doi.org/10.1158/1078-0432.CCR-13-3157

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title = "Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries",

abstract = "PURPOSE: Epstein-Barr virus-positive (EBV(+)) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV(+) DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).RESULTS: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV(+) DLBCL from patients with EBV-negative (EBV(-)) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV(+) DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV(+) DLBCL versus EBV(-) DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV(+) DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.CONCLUSIONS: The clinical characteristics of patients with EBV(+) versus EBV(-) DLBCL are similar and EBV infection does not predict a worse outcome. EBV(+) DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV(+) DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338-49. {\textcopyright}2014 AACR.",

author = "Ok, {Chi Young} and Ling Li and Xu-Monette, {Zijun Y} and Carlo Visco and Alexander Tzankov and Manyam, {Ganiraju C} and Santiago Montes-Moreno and Karen Dybk{\ae}r and April Chiu and Attilio Orazi and Youli Zu and Govind Bhagat and Jiayu Chen and Richards, {Kristy L} and Hsi, {Eric D} and Choi, {William W L} and {van Krieken}, {J Han} and Jooryung Huh and Weiyun Ai and Maurilio Ponzoni and Ferreri, {Andr{\'e}s J M} and Farnen, {John P} and M{\o}ller, {Michael B} and Bueso-Ramos, {Carlo E} and Miranda, {Roberto N} and Winter, {Jane N} and Piris, {Miguel A} and Medeiros, {L Jeffrey} and Young, {Ken H}",

year = "2014",

month = may,

day = "1",

doi = "10.1158/1078-0432.CCR-13-3157",

language = "English",

volume = "20",

pages = "2338--2349",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "9",

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Ok, CY, Li, L, Xu-Monette, ZY, Visco, C, Tzankov, A, Manyam, GC, Montes-Moreno, S, Dybkær, K, Chiu, A, Orazi, A, Zu, Y, Bhagat, G, Chen, J, Richards, KL, Hsi, ED, Choi, WWL, van Krieken, JH, Huh, J, Ai, W, Ponzoni, M, Ferreri, AJM, Farnen, JP, Møller, MB, Bueso-Ramos, CE, Miranda, RN, Winter, JN, Piris, MA, Medeiros, LJ & Young, KH 2014, 'Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries', Clinical Cancer Research, vol. 20, no. 9, pp. 2338-2349. https://doi.org/10.1158/1078-0432.CCR-13-3157

TY - JOUR

T1 - Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries

AU - Ok, Chi Young

AU - Li, Ling

AU - Xu-Monette, Zijun Y

AU - Visco, Carlo

AU - Tzankov, Alexander

AU - Manyam, Ganiraju C

AU - Montes-Moreno, Santiago

AU - Dybkær, Karen

AU - Chiu, April

AU - Orazi, Attilio

AU - Zu, Youli

AU - Bhagat, Govind

AU - Chen, Jiayu

AU - Richards, Kristy L

AU - Hsi, Eric D

AU - Choi, William W L

AU - van Krieken, J Han

AU - Huh, Jooryung

AU - Ai, Weiyun

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J M

AU - Farnen, John P

AU - Møller, Michael B

AU - Bueso-Ramos, Carlo E

AU - Miranda, Roberto N

AU - Winter, Jane N

AU - Piris, Miguel A

AU - Medeiros, L Jeffrey

AU - Young, Ken H

PY - 2014/5/1

Y1 - 2014/5/1

N2 - PURPOSE: Epstein-Barr virus-positive (EBV(+)) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV(+) DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).RESULTS: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV(+) DLBCL from patients with EBV-negative (EBV(-)) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV(+) DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV(+) DLBCL versus EBV(-) DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV(+) DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.CONCLUSIONS: The clinical characteristics of patients with EBV(+) versus EBV(-) DLBCL are similar and EBV infection does not predict a worse outcome. EBV(+) DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV(+) DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338-49. ©2014 AACR.

AB - PURPOSE: Epstein-Barr virus-positive (EBV(+)) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV(+) DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).RESULTS: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV(+) DLBCL from patients with EBV-negative (EBV(-)) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV(+) DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV(+) DLBCL versus EBV(-) DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV(+) DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.CONCLUSIONS: The clinical characteristics of patients with EBV(+) versus EBV(-) DLBCL are similar and EBV infection does not predict a worse outcome. EBV(+) DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV(+) DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338-49. ©2014 AACR.

U2 - 10.1158/1078-0432.CCR-13-3157

DO - 10.1158/1078-0432.CCR-13-3157

M3 - Journal article

C2 - 24583797

SN - 1078-0432

VL - 20

SP - 2338

EP - 2349

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 9

ER -

Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries

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