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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3322-3329.
Prepublished online as a Blood First Edition Paper on August 8, 2008; DOI 10.1182/blood-2008-04-154070.
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Submitted April 29, 2008
Accepted July 26, 2008
Mono-allelic TP53 inactivation is associated with poor prognosis in CLL:
Results from a detailed genetic characterization with long term follow-up
Thorsten Zenz, Alexander Krober, Katrin Scherer, Sonja Habe, Andreas Buhler, Axel Benner, Tina Denzel, Dirk Winkler, Jennifer Edelmann, Carsten Schwanen, Hartmut Dohner, and Stephan Stilgenbauer*
Internal Medicine III, University of Ulm, Ulm, Germany
Department of Biostatistics, DKFZ, Heidelberg, Germany
* Corresponding author; email: stephan.stilgenbauer{at}uniklinik-ulm.de.
The exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11).
Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n=18) (p=0.0019), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs. 69 months (p= P<0.0001)). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months (n=13), TP53 mutation only (5.5 months (n=5)) and 17p deletion only (5.4 months (n=3)). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy suggesting that there may be patients where this treatment is potentially harmful.
TP53 mutations are associated with poor survival once they occur in CLL. The demonstration of clonal evolution under selective pressure supports the biological significance of TP53 mutations in CLL.
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