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.

Department of Cancer Studies and Molecular Medicine MRC Toxicology Unit University of Leicester UK

Department of Clinical and Experimental Medicine Linköping University Sweden

Department of Hematology Royal Bournemouth Hospital UK

Department of Hematology University Hospital University of Duisburg Essen Essen Germany

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Sweden

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 3 University of Ulm Germany

Department of Translational Oncology National Center for Tumor Diseases Heidelberg Germany Department of Internal Medicine 5 University Hospital Heidelberg Germany

Division of Biostatistics German Cancer Research Center Heidelberg Germany

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont Novara Italy

Institute of Hematology and Oncology Department of Hematology Hospital Clínic IDIBAPS University of Barcelona Spain

Laboratory for Immunological and Molecular Cancer Research University Clinics of Internal Medicine 3 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

Ludwig Institute for Cancer Research University of Oxford UK

University Hospital Brno and Central European Institute of Technology Masaryk University Brno Czech Republic

See more in PubMed

Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, et al. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet. 2008;40(10):1204–10 PubMed

Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M, Mansouri M, et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet. 2010;42(2):132–6 PubMed PMC

Di Bernardo MC, Broderick P, Catovsky D, Houlston R. Common genetic variation contributes significantly to the risk of developing chronic lymphocytic leukemia. Haematologica. 2013;98(3):e23–4 PubMed PMC

Slager SL, Skibola CF, Di Bernardo MC, Conde L, Broderick P, McDonnell SK, et al. Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia. Blood. 2012;120(4):843–6 PubMed PMC

Gryshchenko I, Hofbauer S, Stoecher M, Daniel PT, Steurer M, Gaiger A, et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol. 2008;26(14):2252–7 PubMed

Kaderi MA, Mansouri M, Zainuddin N, Cahill N, Gunnarsson R, Jansson M, et al. Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia. Leuk Res. 2010;34(3):335–9 PubMed

Majid A, Richards T, Dusanjh P, Kennedy DBJ, Miall F, Gesk S, et al. TP53 codon 72 polymorphism in patients with chronic lymphocytic leukaemia: identification of a subgroup with mutated IGHV genes and poor clinical outcome. Br J Haematol. 2011; 153(4):533–5 PubMed

Rasi S, Forconi F, Bruscaggin A, Sozzi E, Gaidano G, Rossi D. Impact of the host genetic background on prognosis of chronic lymphocytic leukemia. Blood. 2010;115(5):1106–7 PubMed

Willander K, Ungerback J, Karlsson K, Fredrikson M, Soderkvist P, Linderholm M. MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia. Eur J Haematol. 2010;85(3):251–6 PubMed

Zenz T, Benner A, Stilgenbauer S. MDM2 promotor polymorphism and disease characteristics in CLL. Leuk Res. 2010;34(5):578–9 PubMed

Zenz T, Habe S, Benner A, Kienle D, Dohner H, Stilgenbauer S. The MDM2 - 309 T/G promoter single nucleotide polymorphism does not alter disease characteristics in chronic lymphocytic leukemia. Haematologica. 2008; 93(7):1111–3 PubMed

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12):5446–56 PubMed PMC

Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010;10(1):37–50 PubMed

Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119(5):591–602 PubMed

Bond GL, Hu W, Levine A. A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res. 2005; 65(13):5481–4 PubMed

Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and cancer risk: a combined analysis. Carcinogenesis. 2007; 28(11):2262–7 PubMed

Zenz T, Mohr J, Edelmann J, Sarno A, Hoth P, Heuberger M, et al. Treatment resistance in chronic lymphocytic leukemia: the role of the p53 pathway. Leuk Lymphoma 2009; 50(3):510–3 PubMed

Zenz T, Mertens D, Dohner H, Stilgenbauer S. Importance of genetics in chronic lymphocytic leukemia. Blood Rev. 2011;25(3):131–7 PubMed

Asslaber D, Pinon JD, Seyfried I, Desch P, Stocher M, Tinhofer I, et al. microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. Blood. 2010;115(21):4191–7 PubMed

Stewart LA, Tierney JF. To IPD or not to IPD¿ Eval Health Prof. 2002;25(1):76–97 PubMed

Lahiri O, Harris S, Packham G, Howell M. p53 pathway gene single nucleotide polymorphisms and chronic lymphocytic leukemia. Cancer Genet Cytogenet. 2007; 179(1):36–44 PubMed

Malek SN. MDM2-SNP 309 allele status does not affect sensitivity to MDM2 inhibitors in CLL. Blood. 2008;112(5):2169

Saddler C, Ouillette P, Kujawski L, Shangary S, Talpaz M, Kaminski M, et al. Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia. Blood. 2008;111(3):1584–93 PubMed

Therneau TM, Grambsch PM, Pankratz VS. Penalized survival models and frailty. J Comp Graph Stat. 2003;12(1):156–75

Therneau TM, Grambsch PM. Modeling survival data: Extending the Cox model. 1st ed New York: Springer; 2000. p. 261–87

Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61(10):991–6 PubMed

Grochola LF, Zeron-Medina J, Meriaux S, Bond GL. Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb Perspect Biol. 2010;2(5):a001032. PubMed PMC

Post SM, Quintas-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG, et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell. 2010;18(3):220–30 PubMed PMC

Mhaskar AR, Quinn G, Vadaparampil S, Djulbegovic B, Gwede CK, Kumar A. Timing of first-line cancer treatments - early versus late - a systematic review of phase III randomized trials. Cancer Treat Rev. 2010;36(8):621–8 PubMed

Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma. 2009;50(5):764–72 PubMed

Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst. 1999;91(10):861–8 PubMed

Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2006;3:CD004270. PubMed PMC

Dong HJ, Fang C, Fan L, Zhu DX, Wang DM, Zhu HY, et al. MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL. Int J Cancer. 2012;130(9):2054–61 PubMed