11q & 17p Characterize Discordance of ZAP-70 & VH Mutation

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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

Kröber , Johannes Bloehdorn , Sebastian Hafner , s

Bühler , Till Seiler , Dirk Kienle , Dirk Winkler , Markus

Bangerter , F. Schlenk , Axel Benner , Lichter ,

Hartmut Döhner , and Stephan Stilgenbauer *

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.

* To whom correspondence should be addressed. E-mail:

stephan.stilgenbauer@...

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.