Originally published as JCO Early Release 10.1200/JCO.2005.03.4264 on January 17 2006

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BCL2 Expression Is a Prognostic Marker for the Activated B-Cell–Like Type of Diffuse Large B-Cell Lymphoma

From the Leukemia/Lymphoma Molecular Profiling Project, Departments of Pathology and Microbiology, Genetics, Internal Medicine, and Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; Metabolism Branch and Laboratory of Pathology, Center for Cancer Research, and Biometrics Research Branch, Department of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Pathology, University of Arizona, Tucson, AZ; Departments of Pathology and Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Department of Pathology, University of Würzburg, Würzburg, Germany; Department of Pathology, Hospital Clinic, University of Barcelona, Barcelona, Spain; and Department of Pathology, Norwegian Radium Hospital, Oslo, Norway

Address reprint requests to Wing C. Chan, MD, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-3135; e-mail: jchan{at}unmc.edu

BACKGROUND: The role of BCL2 as a predictor of survival in diffuse large B-cell lymphoma (DLBCL) is controversial. DLBCL is heterogeneous, and the expression of BCL2 is variable within the two major subgroups of DLBCL, germinal center B-cell–like (GCB) and activated B-cell–like (ABC) DLBCL, as well as primary mediastinal DLBCL.

PATIENTS AND METHODS: In this study, we investigated the correlation of BCL2 expression with survival in the two major subgroups of DLBCL, as well as the mechanisms of BCL2 expression.

RESULTS: There was no significant correlation between BCL2 protein expression and overall survival within the GCB subgroup, but BCL2 expression had a significant adverse effect on overall survival within the ABC subgroup (P = .008). This correlation was also observed at the mRNA level (P < .04). The difference remained significant when the analyses were performed at different cutoff values. The t(14;18) was frequently observed in the GCB subgroup and was highly associated with BCL2 expression. Patients with ABC DLBCL did not exhibit t(14;18) but had a markedly higher frequency of chromosome 18q21 amplification, on which BCL2 resides. Thus, alternative mechanisms such as 18q21 amplification or activation of the nuclear factor-kappa B pathway, as reported previously, seem to be mainly responsible for the upregulation of BCL2 expression in the ABC subgroup.

CONCLUSION: Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.

Supported in part by US Public Health Service Grant Nos. CA36727 and CA84967 awarded by the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.

Both J.I. and V.T.N. contributed equally to this work.

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

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