MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis
Axel Benner,
Larry Mansouri,
Davide Rossi,
Aneela Majid,
Kerstin Willander,
Anton Parker,
Gareth Bond,
Sarka Pavlova,
Holger Nückel,
Olaf Merkel,
Paolo Ghia,
Emili Montserrat,
Mohd Arifin Kaderi,
Richard Rosenquist,
Gianluca Gaidano,
Martin J.S. Dyer,
Peter Söderkvist,
Mats Linderholm,
David Oscier,
Zuzana Tvaruzkova,
Sarka Pospisilova,
Ulrich Dührsen,
Richard Greil,
Hartmut Döhner,
Stephan Stilgenbauer,
Thorsten Zenz
Affiliations
Axel Benner
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
Larry Mansouri
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
Davide Rossi
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Aneela Majid
Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, UK
Kerstin Willander
Department of Clinical and Experimental Medicine, Linköping University, Sweden
Anton Parker
Department of Hematology, Royal Bournemouth Hospital, UK
Gareth Bond
Ludwig Institute for Cancer Research, University of Oxford, UK
Sarka Pavlova
University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Holger Nückel
Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany
Olaf Merkel
Laboratory for Immunological and Molecular Cancer Research, University Clinics of Internal Medicine III with Hematology, Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelus Medical University, Salzburg, Austria
Paolo Ghia
Laboratory of B Cell Neoplasia, Division of Molecular Oncology, Ospedale San Raffaele, Istituto Scientifico San Raffale, Fondazione Centro San Raffaele, Università Bita-Salute San Raffaele, Milan, Italy
Emili Montserrat
Institute of Hematology and Oncology, Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona, Spain
Mohd Arifin Kaderi
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden;Department of Biomedical Sciences, Kull Allied Health Sciences, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
Richard Rosenquist
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Martin J.S. Dyer
Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, UK
Peter Söderkvist
Department of Clinical and Experimental Medicine, Linköping University, Sweden
Mats Linderholm
Department of Clinical and Experimental Medicine, Linköping University, Sweden
David Oscier
Department of Hematology, Royal Bournemouth Hospital, UK
Zuzana Tvaruzkova
University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Sarka Pospisilova
University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Ulrich Dührsen
Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany
Richard Greil
Laboratory for Immunological and Molecular Cancer Research, University Clinics of Internal Medicine III with Hematology, Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelus Medical University, Salzburg, Austria
Hartmut Döhner
Department of Internal Medicine III, University of Ulm, Germany
Stephan Stilgenbauer
Department of Internal Medicine III, University of Ulm, Germany
Thorsten Zenz
Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Internal Medicine V, University Hospital Heidelberg, Germany
A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients’ data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.
