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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Kröber
Alexander
A
Department of Internal Medicine, University of Ulm, Ulm, Germany.
Bloehdorn
Johannes
J
Hafner
Sebastian
S
Bühler
Andreas
A
Seiler
Till
T
Kienle
Dirk
D
Winkler
Dirk
D
Bangerter
Markus
M
Schlenk
Richard F
RF
Benner
Axel
A
Lichter
Peter
P
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D005434:Flow Cytometry; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D015999:Multivariate Analysis; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis / Q000235:genetics*
D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human