title: MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
abstract: 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.
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, UK.
authors.forename: Aneela
authors.initials: A
authors.lastname: Majid
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Willander
authors.affiliation: Department of Hematology, Royal Bournemouth Hospital, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Parker
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Bond
authors.affiliation: University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pavlova
authors.affiliation: Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Nückel
authors.affiliation: 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.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Institute of Hematology and Oncology, Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona, Spain.
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
authors.affiliation: 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.
authors.forename: Mohd Arifin
authors.initials: MA
authors.lastname: Kaderi
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, UK.
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Linderholm
authors.affiliation: Department of Hematology, Royal Bournemouth Hospital, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tvaruzkova
authors.affiliation: University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: 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 thorsten.zenz@nct-heidelberg.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D016208:Databases, Factual / Q000639:trends; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
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