MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis

Research output: Contribution to journalArticle

Authors

  • European Research Initiative on CLL (ERIC)

External organisations

  • Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
  • Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
  • Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
  • Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, UK.
  • Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
  • Department of Hematology, Royal Bournemouth Hospital, UK.
  • Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
  • University Hospital Brno and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
  • Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany.
  • 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.
  • 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.
  • Institute of Hematology and Oncology, Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona, Spain.
  • 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.
  • Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
  • 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.

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.

Bibliographic note

Copyright© Ferrata Storti Foundation.

Details

Original languageEnglish
Pages (from-to)1285-91
Number of pages7
JournalHaematologica
Volume99
Issue number8
Publication statusPublished - Aug 2014
Externally publishedYes

Keywords

  • Adult, Aged, Aged, 80 and over, Cohort Studies, Databases, Factual/trends, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis, Male, Middle Aged, Polymorphism, Single Nucleotide/genetics, Promoter Regions, Genetic/genetics, Proto-Oncogene Proteins c-mdm2/genetics, Young Adult