Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell Lymphoma.
OBJECTIVE
Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL) and examined the prognostic use of detecting EBV infection.


METHODS
HIV-related DLBCL cases diagnosed between 1996 and 2007 within Kaiser Permanente California were identified. Immunohistochemical staining was used to analyze the expression of selected markers that are cell-cycle regulators, B-cell activators, and antiapoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman correlation coefficient. The prognostic use of EBV status was examined in multivariable Cox model adjusting for International Prognostic Index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination.


RESULTS
Seventy HIV-related DLBCL cases were included (31% EBV±). EBV+ tumor was associated with increased expression of BLIMP1 and CD30 and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [HR, 3.3; 95% confidence interval (CI), 1.6-6.6]. Area under the ROC curve showed improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)].


CONCLUSIONS
Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-κB pathway and that detecting tumor EBV status may have prognostic use in HIV-related DLBCLs.
Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Ave, 2nd Floor, Los Angeles, CA 91101, USA. chun.r.chao@kp.org
Chun
C
Chao
Michael J
MJ
Silverberg
Otoniel
O
Martínez-Maza
Margaret
M
Chi
Donald I
DI
Abrams
Reina
R
Haque
Hongbin D
HD
Zha
Michelle
M
McGuire
Lanfang
L
Xu
Jonathan
J
Said
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000378:metabolism / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis; D018122:B7-1 Antigen / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D017730:Ki-1 Antigen / Q000378:metabolism; D060588:LIM Domain Proteins / Q000378:metabolism; D016483:Lymphoma, AIDS-Related / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000150:complications / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018122:B7-1 Antigen; C084103:BCL6 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017730:Ki-1 Antigen; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1