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MDM2 SNP309 Is Associated With Poor Outcome in B-Cell Chronic Lymphocytic Leukemia

Irina Gryshchenko, Sebastian Hofbauer, Markus Stoecher, Peter T. Daniel, Michael Steurer, Alexander Gaiger, Karin Eigenberger, Richard Greil, Inge Tinhofer

From the Laboratory for Immunological and Molecular Cancer Research, Third Medical Department at the Salzburg General Hospital and the Paracelsus Private Medical University, Salzburg; Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; and Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Berlin-Buch, Germany

Corresponding author: Inge Tinhofer, PhD, Laboratory for Immunological and Molecular Cancer Research, Third Medical Department at the Salzburg University Hospital, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria; e-mail: i.tinhofer{at}salk.at

	ABSTRACT

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Purpose A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has been negatively associated with onset and outcome of disease in solid tumors. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL.

Patients and Methods The frequency of SNP309 T/T, T/G, or G/G genotypes and the p53 status (wild type, mutated, or deleted) were assessed and correlated with clinical outcome in 140 B-CLL patients and a second independent cohort. In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 protein expression level in B-CLL cells was evaluated by immunoblotting.

Results A significant negative association of the SNP309 T/G and G/G genotypes with overall survival was seen (T/G genotype, relative risk = 3.7; 95% CI, 1.2 to 11.5; P = .02; G/G genotype, relative risk = 9.1; 95% CI, 2.4 to 35.1; P = .001), but no correlation with incidence or onset of B-CLL was observed. The influence of the heterozygous SNP309 T/G genotype on treatment-free survival depended on the p53 status but not on the CD38, Zap-70, or IgVH mutational status or Rai stage of B-CLL patients. The unfavorable SNP309 T/G and G/G genotypes were associated with a gene-dosage–dependent increase of MDM2 expression.

Conclusion The MDM2 SNP309 genotype influencing MDM2 expression levels was identified as an additional independent risk factor in B-CLL. Targeting MDM2-p53 interactions might emerge as a successful treatment strategy for B-CLL.

	INTRODUCTION

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In normal cells, protection of the genome integrity and prevention of tumor formation is exerted by p53¹ because its expression and transcriptional activity is induced by DNA damage or oncogene activation. Therefore, loss of function of p53 by mutation and/or deletion can result in tumorigenesis, which can explain the high frequency of aberrations in the p53 gene in tumors. Recent data suggest that, beside mutation and/or deletion of p53, variations in critical modulators of the p53 pathway might influence p53 functions and thus increase susceptibility to and progression of neoplastic disease. The search for such variations primarily focused on MDM2, a negative regulator of p53.² Recently, a single nucleotide polymorphism (SNP), a T to G change at the 309th nucleotide in the first intron of the MDM2 intronic promoter (referred to as SNP309 in this study), was described.³ This polymorphism, which leads to increased levels of MDM2 mRNA and protein, was significantly associated with early development of solid tumors and drug resistance, suggesting that the MDM2 genotype might influence not only tumorigenesis, but also treatment outcome.³

In B-cell chronic lymphocytic leukemia (B-CLL), loss of p53 function by deletion of chromosome 17p (del17p) or p53 mutations has been shown to contribute to a more aggressive course of disease⁴ and to resistance to therapy.^5,6 Overexpression of MDM2 was found in 28% of B-CLL patients.⁷ Aberrant expression of MDM2 might lead to p53 dysfunction and reduced response to chemotherapy. The role of SNP309 in aberrant interactions of MDM2 and p53 that inactivate the p53 pathway in B-CLL has not been addressed before. Therefore, we analyzed the association of SNP309 with clinical course of B-CLL and its interaction with the p53 status of tumor cells.

	PATIENTS AND METHODS

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Patients and Samples
The study was approved by the local ethics committee and conducted according to the Declaration of Helsinki. After obtaining informed patient consent, 140 consecutive, unselected B-CLL patients seen at the Department of Hematology and Oncology of the University Hospitals of Salzburg and Innsbruck, Austria, between October 1999 and December 2006 (cohort I), were included in this retrospective study. According to the guidelines of the National Cancer Institute–sponsored working group,⁸ B-CLL was defined by clinical criteria, cellular morphology, and coexpression of CD19, CD5, and CD23 in lymphocytes simultaneously displaying restriction of light-chain rearrangement. Treatment-free survival (TFS) was defined as the period between first diagnosis and first B-CLL–specific treatment. Decisions on treatment were based on the National Cancer Institute working group criteria.⁸ Median observation time of patients in cohort I was 74 months (range, 1 to 328 months). Patient characteristics are listed in Appendix Table A1 (online only). For validation, an additional independent cohort of 111 B-CLL patients from the Vienna University Hospital in Austria (cohort II; median observation time, 41 months; range, 1 to 215 months) was analyzed.

Peripheral-blood mononuclear cells from heparinized blood samples were isolated by density centrifugation and stored in liquid nitrogen for genetic studies. In addition, cells from cohort I were characterized for IgVH mutational status, CD38 and Zap-70 expression levels, and deletion of chromosome 17p13.

SNP309 Genotyping
Genomic DNA was isolated using QIAamp DNA Mini Kit (Qiagen, Valencia, CA) according to manufacturer's instructions. SNP309 genotype was detected using two different fluorescent Taqman probes (MDM2-T-FAM and MDM2-G-VIC) to discriminate between the common SNP309 genotype (T/T) and the variant alleles (T/G and G/G), as described previously.³ Briefly, sense primer (MDM2 S, 5`-gga gtt cag ggt aaa ggt cac g-3`), antisense primer (MDM2 AS (5`-gcg cag cgt tca cac tag tg-3`), and the polymorphism-specific primers MDM2-T-FAM (5`-ccg ctT cgg cgc g-3`, for detection of thymidine) and MDM2-G-VIC (5`-ccg ctG cgg cgc g-3`, for detection of guanine at position 309 of the MDM2 promoter region) were used. For reverse transcriptase polymerase chain reaction (PCR), 2x Universal PCR Master Mix No AmpErase UNG (Applied Biosystems, Foster City, CA), primers, and DNA 10 ng were mixed. Conditions for reverse transcriptase PCR were as follows: one cycle at 95°C for 10 minutes and 40 cycles at 95°C for 15 seconds and 60°C for 1 minute at each cycle. Amplification was performed using ABI 7500 Real-Time PCR system (Applied Biosystems). All analyses were performed in duplicates.

Western Blot Analysis
Expression levels of MDM2 were determined by Western blot analysis. Briefly, standard sodium dodecyl sulfate–polyacrylamide gel electrophoresis was performed using 30 µg of total protein per cell lysate, followed by transfer to polyvinylidene difluoride membranes (Millipore, Bedford, MA). The following antibodies were used for detection: mouse anti-MDM2 monoclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-actin polyclonal antibody (Cell Signaling Technology, Danvers, MA), and rabbit antimouse and swine antirabbit peroxidase-conjugated secondary antibodies (both from Dako Cytomation, Glostrup, Denmark). Expression of MDM2 was first normalized to β-actin used as internal protein loading control. The ratios of MDM2 to β-actin signals were then normalized to that of one reference sample included in each Western blot analysis.

Detection of p53 Status
p53 deletion was detected by interphase fluorescent in situ hybridization analysis using a commercially available probe set (Abbott/Vysis, Vienna, Austria) according to the manufacturer's instructions. In addition, tumor DNA was screened for the presence of somatic p53 mutations by single-stranded conformation polymorphism analysis, as described previously.⁵

Statistical Analysis
All statistical analyses were performed using StatView 5.1 (Abacus Concepts Inc, Berkeley, CA). The primary end point of this study was the correlation of the SNP309 genotype with overall survival (OS), the secondary end point was correlation of the SNP309 genotype with TFS. Comparisons of OS and TFS of patients were performed using the Kaplan-Meier method, and significance was determined using the log-rank test. Multivariate analysis to determine the interdependency of SNP309 genotype and the risk parameters of del17p13, CD38, Zap-70, and IgVH mutational status and Rai stage was carried out using Cox proportional hazards regression.

The significance of differences in the onset of B-CLL as determined by the age of B-CLL patients at first diagnosis or in the MDM2 expression levels depending on the SNP309 genotype was determined using a factorial analysis of variance unpaired t test. The distributions of clinical parameters in the cohorts with T/T, T/G, or G/G genotype were compared using the ² test.

	RESULTS

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Impact of SNP309 Genotype on OS in B-CLL
On the basis of previous studies reporting an association between overexpression of MDM2 and solid tumors, we hypothesized that such overexpression in SNP309 T/G or G/G carriers resulting in inactivation of p53 might also influence the course of disease in B-CLL. By immunoblotting, we detected MDM2 protein in B-CLL cells and confirmed the reported correlation of SNP309 genotype with MDM2 expression levels (Figs 1A and FIG 1B; T/T v T/G, P = .039; T/T v G/G, P = .0015; T/G v G/G, P = not significant). We then classified patients into three different subgroups according to their SNP309 genotype and analyzed their OS. As presented in a Kaplan-Meier plot in Figure 1C, patients with the heterozygous (T/G) genotype and homozygous (G/G) SNP309 variants showed a significantly shortened OS when either subgroup was compared with patients with the common (T/T) SNP309 genotype. We also found a significant association between the SNP309 G/G genotype and TFS (Fig 2A) in B-CLL, which was confirmed in an independent cohort of B-CLL patients (cohort II, n = 111; T/T v T/G, P = .6; T/T v G/G, P = .01).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. SNP309 genotypes influencing MDM2 expression levels significantly affect overall survival (OS) in B-cell chronic lymphocytic leukemia. (A) MDM2 expression levels from representative samples are shown. (B) Normalized MDM2 expression levels from samples with different genotype (n = 10 each) are presented. (C) Kaplan-Meier analysis revealed a significant interaction of the SNP309 genotype with OS.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. The interaction of SNP309 with treatment (trt)-free survival in B-cell chronic lymphocytic leukemia depends on the p53 status of patients. (A) All patients or the subgroup of patients with (B) p53 wild type (wt) or (C) p53 deletion were analyzed for the interaction of the SNP309 genotype with treatment-free survival.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Risk for shortened treatment (trt)-free survival in patients with p53 deletion depends on their SNP309 genotype. Patients were classified into (A) low-risk and (B) high-risk groups according to their p53 status and SNP309 genotype and analyzed for treatment-free survival.

Lack of Correlation of SNP309 With Incidence or Onset of B-CLL
A positive association of SNP309 with the incidence of breast cancer,⁹ gastric carcinoma,¹⁰ and lung cancer¹¹ has previously been demonstrated. To find out whether this was also the case with B-CLL, we analyzed the frequency of the different SNP309 genotypes in our B-CLL patient cohort (n = 140) and compared it with a control group of healthy individuals. The distribution of the SNP309 genotype in our patient cohort was as follows: T/T carriers, n = 62 (44.3%); T/G carriers, n = 58 (41.4%); and G/G carriers, n = 20 (14.3%; Appendix Table A1). We also observed such a distribution of SNP309 genotypes in two independent cohorts of 111 B-CLL patients from the Vienna University Hospital and of 149 B-CLL patients from different hospitals in the United Kingdom (data not shown). The distribution of the SNP309 genotypes in all cohorts was not different to that reported for a cohort of 50 healthy volunteers in the initial study by Bond et al.³ Thus, there does not seem to be any correlation between SNP309 genotypes and incidence of B-CLL. We next addressed whether the SNP309 genotype correlates with an early onset of disease in B-CLL as has been shown for soft tissue sarcomas³ and colorectal cancer.¹² We assessed the age of patients at first diagnosis in the subgroups with different SNP309 genotypes. No significant impact of SNP309 genotype on the onset of B-CLL could be detected (data not shown). However, when we compared the distribution of SNP309 genotypes in patient cohorts at distinct Rai stages, we observed a slight accumulation of the more unfavorable genotypes (T/G and G/G) with higher Rai stage (Appendix Table A1).

	DISCUSSION

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Inactivation of the p53 pathway by deletion⁴ or mutation⁵ of the p53 gene has been reported in B-CLL, although at lower frequencies than in other neoplasias. Depending on the phase of disease, frequencies of 5% to 17% for p53 deletions^4,13 and of 10% to 15% for p53 mutations^5,6,14-16 have been demonstrated. Our present data suggest that the role of p53 dysfunctions in the clinical course of B-CLL might be underestimated because, in addition to direct genetic changes within the p53 gene, the p53 signaling pathway may also be disrupted at an additional molecular level in B-CLL. We demonstrated that the SNP within the promoter region of MDM2, which increases MDM2 expression levels³ (Figs 1A and FIG 1B), might contribute to the inactivation of p53 in B-CLL. We observed a negative effect of SNP309 on OS and TFS in B-CLL (Figs 1 to 3), although we did not observe an association between the SNP309 genotypes and incidence or onset of disease (Appendix Table A1). However, this was not an unexpected finding because there is no evidence that inactivation of the p53 pathway is causally related to the development of B-CLL, but rather, it influences its clinical course. Although increased expression levels of MDM2 have been reported previously,⁷ it remains to be determined in future studies whether the MDM2 protein expression level represents a biomarker for the course of disease independent of the SNP309 genotype.

Interestingly, we observed a gene-dosage effect of the SNP309 genotype on TFS that was dependent on the p53 status (Figs 2B and 2C). In cases of wild-type p53, the homozygous but not heterozygous SNP309 variant negatively influenced TFS (Fig 2B). In cases of monoallelic loss of p53, both SNP309 T/G and G/G genotypes were associated with a significantly reduced TFS, which suggests that reduction of p53 gene dosage renders B-CLL cells more susceptible to the negative effect of MDM2 overexpression. A recent study of Li-Fraumeni syndrome patients also revealed a significant association of both SNP309 T/G and G/G genotypes with the onset of solid tumors in patients with p53 germline mutations, whereas in the p53 wild-type group, only a higher prevalence of SNP309 homozygous G/G carriers was observed.¹⁷

In our patient cohort, deletion of p53 only affected one allele, and in all patients, the remaining allele was retained in its wild-type form (Appendix Table A1). That the cellular level of p53 determines the outcome of cells is not surprising because, depending on whether one or both p53 alleles are functional, there is a significant difference in the gene expression profile of cells even in the absence of cellular stress.¹⁸ Interestingly, in our study, despite reduction of p53 levels in del17p patients with monoallelic loss of p53, no significant difference in TFS compared with patients with wild-type p53 was observed when the former group were carriers of the favorable SNP309 (T/T) genotype (Fig 3). This observation certainly has to be confirmed in a larger patient cohort in future studies. The interaction of the SNP309 genotype with p53 functions in patients with p53 deletions might also explain why a recent study reported only an imperfect correlation between the presence of p53 deletion/mutation and the inability of B-CLL cells to upregulate p53 target genes after -irradiation.¹⁹

In conclusion, we identified the SNP309 genotype as an additional risk factor for reduced OS and TFS in B-CLL. This might be explained by aberrant MDM2-p53 interactions leading to p53 inactivation in the unfavorable SNP309 genotypes. If analyses in larger patient cohorts corroborate our findings, the integration of novel agents that target the MDM2-p53 interaction might emerge as a particularly successful treatment strategy for B-CLL.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 
Conception and design: Richard Greil, Inge Tinhofer

Provision of study materials or patients: Peter T. Daniel, Alexander Gaiger, Richard Greil

Collection and assembly of data: Irina Gryshchenko, Sebastian Hofbauer, Markus Stoecher, Peter T. Daniel, Michael Steurer, Alexander Gaiger, Karin Eigenberger

Data analysis and interpretation: Irina Gryshchenko, Richard Greil, Inge Tinhofer

Manuscript writing: Inge Tinhofer

Final approval of manuscript: Richard Greil

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 

	GLOSSARY

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 

SNP (single nucleotide polymorphism):

Genetic polymorphisms are natural variations in the genomic DNA sequence present in greater than 1% of the population, with SNP representing DNA variations in a single nucleotide. SNPs are being widely used to better understand disease processes, thereby paving the way for genetic-based diagnostics and therapeutics.

p53:

The normal function of p53 is to act as a transcriptional activator of genes with a p53-binding site and an inhibitor of genes lacking a p53 binding site. Expression of high levels of wild-type p53 is associated with cell cycle arrest and apoptosis. Mutations in p53 are seen in several tumors.

MDM2:

An E3 ubiquitin ligase that recognizes the N-terminal activation domain (TAD) of proteins belonging to the p53 family. By blocking the ability of p53 to associate with factors involved in protein transcription, the MDM2 interaction with p53 prevents transcriptional activation. Further, interaction with p53 leads to ubiquitinylation and subsequent degradation of p53. (See Proteasome and Ubiquitin).

	ACKNOWLEDGMENTS

 
We thank C. Mannhalter, PhD, Professor of Medicine, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna for her support at DNA isolation and storage. We also thank Rajam Csordas-Iyer for critical reading and editorial assistance.

	NOTES

 
Supported by Grant No. 05/02/014 from the PMU Forschungsgesellschaft (I.G.), Grants No. P16153 [GenBank] (I.T.) and SFB021 (R.G.) from the Austrian Science Foundation, and grants from the Province of Salzburg (R.G. and I.T.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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6. Wattel E, Preudhomme C, Hecquet B, et al: p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148-3157, 1994[Abstract/Free Full Text]

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8. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored working group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996[Free Full Text]

9. Bond GL, Hirshfield KM, Kirchhoff T, et al: MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66:5104-5110, 2006[Abstract/Free Full Text]

10. Ohmiya N, Taguchi A, Mabuchi N, et al: MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. J Clin Oncol 24:4434-4440, 2006[Abstract/Free Full Text]

11. Lind H, Zienolddiny S, Ekstrom PO, et al: Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int J Cancer 119:718-721, 2006[CrossRef][Medline]

12. Menin C, Scaini MC, De Salvo GL, et al: Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst 98:285-288, 2006[Abstract/Free Full Text]

13. Thornton PD, Gruszka-Westwood AM, Hamoudi RA, et al: Characterisation of TP53 abnormalities in chronic lymphocytic leukaemia. Hematol J 5:47-54, 2004[CrossRef][Medline]

14. Gaidano G, Ballerini P, Gong JZ, et al: p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 88:5413-5417, 1991[Abstract/Free Full Text]

15. Fenaux P, Preudhomme C, Lai JL, et al: Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: A report on 39 cases with cytogenetic analysis. Leukemia 6:246-250, 1992[Medline]

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17. Ruijs MW, Schmidt MK, Nevanlinna H, et al: The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15:110-114, 2007[CrossRef][Medline]

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Submitted March 1, 2007; accepted January 18, 2008.

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