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Received on April 3, 2007
Accepted on July 23, 2007
Molecular Diagnostics and Genetics |
1 Laboratory of Experimental Hematology, Brussels, Belgium, and Functional Genomics and Translational Research Unit Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium, and Machine Learning Group, Faculty of Sciences, Université Libre de Bruxelles, Brussels, Belgium
2 Functional Genomics and Translational Research Unit Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium, and Machine Learning Group, Faculty of Sciences, Université Libre de Bruxelles, Brussels, Belgium
3 Laboratory of Experimental Hematology, Brussels, Belgium
* To whom correspondence should be addressed. E-mail: bstamato{at}ulb.ac.be.
Background: Chronic lymphocytic leukemia (CLL) is heterogeneous with respect to prognosis and clinical outcome. The mutational status of the immunoglobulin variable heavy chain region (IGHV) has been used to classify patients into 2 groups in terms of overall survival (OS) and clinical characteristics, but the labor-intensive nature and the cost of this time-consuming analysis has prompted investigations of surrogate markers.
Methods: We developed a standardized quantitative real-time reverse transcription-PCR (qPCR) method to measure zeta-chain (TCR)-associated protein kinase (ZAP70) mRNA in purified CD19+ cells. We evaluated this and other methods (flow cytometry analyses of ZAP70 and CD38 proteins and qPCR analysis of lipoprotein lipase mRNA) in a cohort of 108 patients (median follow-up, 82 months) to evaluate any associations with IGHV mutational status, OS, and treatment-free survival (TFS).
Results: The association between qPCR-measured ZAP70 and IGHV mutational status was statistically significant [
2 (1) = 50.95; P <0.0001], and the value of Cramer's V statistic (0.72) indicated a very strong relation. This method also demonstrated sensitivity, specificity, and positive and negative predictive values of 87.8%, 85.7%, 87.5%, and 86%, respectively. ZAP70 expression was significantly associated with OS (P = 0.0021) and TFS (P <0.0001). ZAP70+ patients had significantly shorter median TFS (24 months) than ZAP70- patients (157 months) (P <0.0001). Moreover, qPCR-measured ZAP70 expression has greater prognostic power than IGHV mutational status and the other prognostic markers tested.
Conclusions: ZAP70 mRNA quantification via qPCR is a strong surrogate marker of IGHV mutational status and a powerful prognostic variable.
The following articles in journals at HighWire Press have cited this article:
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  B. Stamatopoulos, B. Haibe-Kains, C. Equeter, N. Meuleman, A. Soree, C. De Bruyn, D. Hanosset, D. Bron, P. Martiat, and L. Lagneaux Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA Haematologica, June 1, 2009; 94(6): 790 - 799. [Abstract] [Full Text] [PDF]
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 B. Stamatopoulos, N. Meuleman, B. Haibe-Kains, P. Saussoy, E. Van Den Neste, L. Michaux, P. Heimann, P. Martiat, D. Bron, and L. Lagneaux microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification Blood, May 21, 2009; 113(21): 5237 - 5245. [Abstract] [Full Text] [PDF]
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 T. J. Kipps Chronic Lymphocytic Leukemia: Advances in Assessing Prognosis and Therapy ASCO Educational Book, January 1, 2009; 2009(1): 385 - 393. [Abstract] [Full Text] [PDF]
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A. W. Hauswirth and U. Jager Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia Haematologica, January 1, 2008; 93(1): 14 - 19. [Full Text] [PDF]
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