Originally published as JCO Early Release 10.1200/JCO.2005.03.7184 on January 17 2006

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Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

From the Department of Internal Medicine, University of Ulm; Hämatologische-onkologische Praxis Brudler, Heinrich, Bangerter, Augsburg; Central Unit Biostatistics, DKFZ; Division of Molecular Genetics, DKFZ, Heidelberg, Germany

Address reprint requests to Stephan Stilgenbauer, MD, Department of Internal Medicine III, University of Ulm, Robert-Koch-Straße 8, 89081 Ulm, Germany; e-mail: stephan.stilgenbauer{at}uniklinik-ulm.de

PURPOSE: Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance.

PATIENTS AND METHODS: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact.

RESULTS: ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors.

CONCLUSION: There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Supported by the Sander-Stiftung Grants No. 2003.086.1 and 2001.04.02, Deutsche Krebshilfe Grant No. 106116, and Deutsche José Carreras Leukämie-Stiftung e. V. Grant No. R 05/25.

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

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