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MDM2 SNP309 Is Associated With Poor Outcome in B-Cell Chronic Lymphocytic Leukemia

Irina Gryshchenko, Sebastian Hofbauer, Markus Stoecher, Peter T. Daniel, Michael Steurer, Alexander Gaiger, Karin Eigenberger, Richard Greil, Inge Tinhofer

From the Laboratory for Immunological and Molecular Cancer Research, Third Medical Department at the Salzburg General Hospital and the Paracelsus Private Medical University, Salzburg; Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; and Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Berlin-Buch, Germany

Corresponding author: Inge Tinhofer, PhD, Laboratory for Immunological and Molecular Cancer Research, Third Medical Department at the Salzburg University Hospital, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria; e-mail: i.tinhofer{at}salk.at

Purpose A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has been negatively associated with onset and outcome of disease in solid tumors. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL.

Patients and Methods The frequency of SNP309 T/T, T/G, or G/G genotypes and the p53 status (wild type, mutated, or deleted) were assessed and correlated with clinical outcome in 140 B-CLL patients and a second independent cohort. In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 protein expression level in B-CLL cells was evaluated by immunoblotting.

Results A significant negative association of the SNP309 T/G and G/G genotypes with overall survival was seen (T/G genotype, relative risk = 3.7; 95% CI, 1.2 to 11.5; P = .02; G/G genotype, relative risk = 9.1; 95% CI, 2.4 to 35.1; P = .001), but no correlation with incidence or onset of B-CLL was observed. The influence of the heterozygous SNP309 T/G genotype on treatment-free survival depended on the p53 status but not on the CD38, Zap-70, or IgVH mutational status or Rai stage of B-CLL patients. The unfavorable SNP309 T/G and G/G genotypes were associated with a gene-dosage–dependent increase of MDM2 expression.

Conclusion The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL.

Supported by Grant No. 05/02/014 from the PMU Forschungsgesellschaft (I.G.), Grants No. P16153 [GenBank] (I.T.) and SFB021 (R.G.) from the Austrian Science Foundation, and grants from the Province of Salzburg (R.G. and I.T.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Comprehensive Single Nucleotide Polymorphism Study Supports the Role of MDM2 in p53-Competent Chronic Lymphocytic Leukemia
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