MDM2 promotor polymorphism and disease characteristics in CLL

Richard Greil

MDM2 promotor polymorphism and disease characteristics in CLL

Richard Greil

2010, Leukemia Research

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This research investigates the role of MDM2 promoter polymorphism (SNP309) in the characteristics of Chronic Lymphocytic Leukemia (CLL). The SNP is linked to the modulation of the p53 pathway, with implications on disease onset and the prognosis of various cancers. However, the study emphasizes the need for large-scale individual patient data meta-analyses to validate the prognostic significance of MDM2-SNP309 in CLL, as smaller studies have produced inconsistent results regarding polymorphisms in cancer outcomes.

Leukemia Research 34 (2010) 578–579 Contents lists available at ScienceDirect Leukemia Research journal homepage: www.elsevier.com/locate/leukres Guest Editorial MDM2 promotor polymorphism and disease characteristics in CLL a r t i c l e i n f o Keywords: MDM2 CLL SNP A number of years ago, a single nucleotide polymorphism (SNP) in the MDM2 promotor region (IVS1 + 309) was identified, which was shown to attenuate the p53 pathway directly by influencing MDM2 transcript and protein levels (Bond et al.) (Fig. 1) [1]. Patients with the Li-Fraumeni syndrome developed cancers 10–12 years earlier, when carrying the G/G allele of MDM2-SNP309. In addition, the SNP309 also correlated with the number of independent primary tumours developed by patients with sporadic soft tissue sarcoma [1]. This important finding has led to the investigation of the role of the MDM2 polymorphism in a variety of different cancers with partially conflicting results. A recent meta-analysis found no effect of the polymorphism in colorectal and breast cancer, but showed a small but significant predisposition to lung cancer [2]. Most positive findings on the MDM2 SNP genotype were related to disease onset rather than outcome in line with the initial description [2]. Because of the exceptionally well documented functional consequences of the MDM2-SNP309 and the important prognostic role of p53 in CLL it appeared logical to study the MDM2-SNP309 in CLL [3–6]. In addition, because of the high incidence of trisomy 12 (MDM2 locus) any effect of the polymorphism could have been expected to be increased based on gene dosage. In this issue Kaderi and colleagues report on a large analysis studying potential effects of the MDM2 polymorphism in a cohort of CLL patients (n = 418) from Sweden [7]. It is important to note that the multiple clinical and biological prognostic markers were available for the cohort and the established factors retained their prognostic value, suggesting that the cohort was not significantly biased. In contrast, the authors could not detect an association between MDM2 promotor polymorphism genotype and time to first treatment and overall survival. Age at onset was also similar across MDM2-SNP309 genotype groups, although a separate analysis comparing age of onset was not shown. The authors have rightly avoided extensive subgroup analysis, which often are a source of misleading findings. The results of Kaderi et al. [7] represent an important advance and confirm previous studies by other groups showing no discernable prognostic effect of the SNP in CLL [8,9]. In contrast, a recent report, by Gryshchenko et al. analyzed retrospectively 140 patients from two clinical centers and found a striking effect of the MDM2-309 GG genotype on clinical outcome (overall survival and treatment-free survival) as well as on MDM2 protein expression [9]. A univariate association with TFS could also 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.07.015 be shown for a second independent cohort of 111 patients but the findings from the validation cohort were not shown in detail. A potential negative prognostic effect of the heterozygous genotype appeared to be restricted to the subgroup of patients with 17p deletion. CLL patients with 17p deletion have repeatedly been shown to have a dismal prognosis and the presence of a 17p deletion is the most powerful predictor of poor outcome [4,5]. In this respect it is somewhat surprising to note that Gryshchenko et al. found the GG genotype to be associated with an even greater risk of death or need for treatment compared to that of patients with 17p deletion [9]. It is also noteworthy that the authors did not find TP53 mutations in any of their patients with 17p deletion which is in contrast to many other reports [6,10,11]. Since subgroup analyses (e.g. 17p−) have to be considered with caution in studies that were relatively small to begin with, the final word on any role of the MDM2-309 polymorphism in CLL will have to come from individual patient data (IPD) meta-analysis. This approach appears to be missing from the relevant CLL literature, but since the overall patient number now adds up to almost 1500, this approach should be encouraged. In general, the story of prognostic impact of various polymorphisms in CLL (and many other diseases) is one of initial description of an association and the failure to reproduce the findings in independent data sets (e.g. BAX, PBX27, BCL2). The initial studies often stemmed from relatively small, hypothesis generating studies, which have not included validation cohorts. In many if not all instances the findings were not reproduced in subsequent, mostly larger studies. Therefore in addition to the scientific explanation why a particular SNP of a given gene may influence disease characteristics, some statistical issues should be discussed that help to judge and design future studies. Since the effect of a given polymorphism is likely to be small, large studies are generally needed. The current study by Richard Rosenquist’s group reiterates the need for large cohorts when testing for what might be a subtle impact on disease characteristics in most cases. In order to visualize the problem of sample size, Fig. 2 shows the power calculation as a function of total sample size and hazard ratio given a hypothetical MDM2 genotype frequency distribution of (T/T: 0.4, G/T: 0.5, G/G: 0.1) for the comparison of patients with G/G or G/T genotypes with patients with T/T genotype. It is very instructive to see that, if we want to proof the prognostic impact of a particular genotype we can 579 Guest Editorial / Leukemia Research 34 (2010) 578–579 Fig. 1. The MDM2 309 polymorphism changes a T to G at nucleotide 309 of intron 1 close to the p53 response element and creates a higher-affinity DNA-binding site for the transcription factor Sp1 that leads to increased levels of MDM2 RNA and protein in cells. Cell lines homozygous for the G allele express high levels of MDM2 and were shown to have an impaired p53 response after DNA damage with poor induction of p53 and weak p53-induced apoptosis [1] (adapted from Bond and Levine [3]). References Fig. 2. Power calculation as a function of varying hazard ratios and different sample sizes using 10,000 simulations given a hypothetical MDM2 genotype frequency distribution of (T/T: 0.4, G/T: 0.5, G/G: 0.1) for the comparison of patients with G/G or G/T genotypes with patients with T/T genotype. The baseline hazard was again chosen according to the estimated baseline hazard of the of the Ulm cohort(8). The dotted lines correspond to the 5% significance level and a power of 80% as used in many clinical trial sample size calculations. only expect to find strong variables conferring a HR >2 in the size of the cohorts that are commonly used. In contrast, subtle changes, as the ones likely to be exerted by most polymorphisms with HR below 1.4 can only be detected if large cohorts (>500 patients) are investigated. Conflict of interest There are no conflicts of interest to disclose. Acknowledgements T. Zenz, A. Benner, and S. Stilgenbauer wrote the paper. [1] Bond GL, Hu W, Bond EE, 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. [2] Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and cancer risk: a combined analysis. Carcinogenesis 2007;28(11):2262–7. [3] Bond GL, Levine AJ. A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 2007;26(9):1317–23. [4] Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995;85(6):1580–9. [5] Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343(26):1910–6. [6] Zenz T, Krober A, Scherer K, et al. Mono-allelic TP53 inactivation is associated with poor prognosis in CLL: results from a detailed genetic characterization with long term follow-up. Blood 2008. [8] 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. [9] 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. [10] Gryshchenko I, Hofbauer S, Stoecher M, et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol 2008;26(14):2252–7. [11] Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia 2009;23(1):117–24. Thorsten Zenz a , Axel Benner b , Stephan Stilgenbauer a,∗ a Department of Internal Medicine III, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany b Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany ∗ Corresponding author. Tel.: +49 731 50045501; fax: +49 731 50045505. E-mail address: stephan.stilgenbauer@uniklinik-ulm.de (S. Stilgenbauer) 6 July 2009 Available online 25 August 2009

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