Published online 30 November 2009
Haematologica, Vol 95, Issue 1, 102-109 doi:10.3324/haematol.2009.010298
Copyright © 2010 by Ferrata Storti Foundation
Dirk Kienle1 ,
Axel Benner2 ,
Carolin Läufle1 ,
Dirk Winkler1 ,
Christof Schneider1 ,
Andreas Bühler1 ,
Thorsten Zenz1 ,
Annett Habermann1 ,
Ulrich Jäger3 ,
Peter Lichter4 ,
Riccardo Dalla-Favera5 ,
Hartmut Döhner1 ,
Stephan Stilgenbauer1
Haematologica, Vol 95, Issue 1, 102-109 doi:10.3324/haematol.2009.010298
Copyright © 2010 by Ferrata Storti Foundation
Chronic Lymphocytic Leukemia |
Gene expression factors as predictors of genetic risk and survival in chronic lymphocytic leukemia
1 Department of Internal Medicine III, University of Ulm, Germany
2 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
3 Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
4 Division of Molecular Genetics, DKFZ Heidelberg, Germany
5 Institute for Cancer Genetics, Department of Pathology and Genetics and Development, Columbia University, NY, USA
Correspondence: Stephan Stilgenbauer, Department of Internal Medicine III, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany. E-mail: stephan.stilgenbauer{at}uniklinikulm.de
Background: A variety of surrogate markers for genetic features and outcome have been described in chronic lymphocytic leukemia based on gene expression analyses. Previous studies mostly focused on individual markers and selected disease characteristics, which makes it difficult to estimate the relative value of the novel markers. Therefore, in the present study a comprehensive approach was chosen investigating 18 promising, partly novel expression markers in a well characterized cohort of patients with long clinical follow-up and full genetic information (IGHV status, genomic abnormalities).
Design and Methods: Expression markers were evaluated using real-time quantitative reverse transcriptase polymerase chain reaction in CD19+-purified samples from 151 patients. Multivariate analyses were performed to test the markers’ ability to identify patients at genetic risk and as prognostic markers in the context of established prognostic factors.
Results: For individual markers, ZAP70 expression provided the highest rate (81%) of correct assignment of patients at genetic risk (IGHV unmutated, V3-21 usage, 11q- or 17p-), followed by LPL and TCF7 (76% both). The assignment rate was improved to 88% by information from a four-gene combination (ZAP70, TCF7, DMD, ATM). In multivariate analysis of treatment-free survival, IGHV mutation status and expression of ADAM29 were of independent prognostic value besides disease stage. With regards to overall survival, expression of ATM, ADAM29, TCL1, and SEPT10 provided prognostic information in addition to that derived from clinical and genetic factors.
Conclusions: Gene expression markers are suitable for screening but not as surrogates for the information from genetic risk factors. While many individual markers may be associated with outcome, only a few are of independent prognostic significance. With regard to prognosis estimation, the genetic prognostic factors cannot be replaced by the expression markers.
Key words: chronic lymphocytic leukemia, markers, quantitative RT-PCR.
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