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Carcinogenesis Advance Access originally published online on September 7, 2007
Carcinogenesis 2007 28(11):2262-2267; doi:10.1093/carcin/bgm191
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MDM2 SNP309 and cancer risk: a combined analysis

Stefan Wilkening1,*, Justo Lorenzo Bermejo1 and Kari Hemminki1,2

1 Department of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
2 Center for Family and Community Medicine, Karolinska Institute, SE-14183 Huddinge, Sweden

* To whom correspondence should be addressed. Tel: +49 6221 421792; Fax: +49 6221 421810; Email: stefan_wilkening{at}web.de


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 
A paper by Bond et al. reported that a single-nucleotide polymorphism (SNP) in the intronic promoter region of the mouse double minute 2 (MDM2) gene (called SNP309) can significantly change the expression of MDM2 and thereby suppress the p53 pathway. Furthermore, it was shown that SNP309 accelerates tumor formation in Li–Fraumeni patients. This initial report aroused the attention of many researchers, which investigated the role of SNP309 for the risk and the onset of cancer in different tissues. To provide a more robust estimate of the effect of this polymorphism on cancer risk, we combined the available genotype data for breast, colorectal and lung cancers. For breast cancer, we combined the data from 11 studies including 5737 cases and 6703 controls. For colorectal cancer, we combined the data from five studies with 1620 cases and 886 controls. For lung cancer, we performed a fixed-effect meta-analysis from seven studies including 4276 cases and 5318 controls. Our results suggest that the SNP309 variant does not have an impact on the risk of breast [odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.87–1.08] or colorectal cancers (OR = 0.97, 95% CI = 0.76–1.25). However, the combined estimate of the ORs for lung cancer revealed an increased risk for GG versus TT (OR = 1.27, 95% CI = 1.12–1.44). The data show that SNP309 alone has little or no effect on the risk of common cancers, but it might modify the time of tumor onset and prognosis.

Abbreviations: CI, confidence interval; MDM2, mouse double minute 2; OR, odds ratio; SNP, single-nucleotide polymorphism; TP53, tumor protein p53


   Introduction
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 Introduction
Materials and methods
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The human homolog of mouse double minute 2 (MDM2) is a negative regulator of the tumor protein p53 (TP53). MDM2 is a nuclear phosphoprotein that binds to TP53 and inhibits TP53-dependent transcription (1). Over-expression of this gene can result in inactivation of TP53, diminishing its tumor suppressor function (2). MDM2 has also been shown to promote tumor growth in a TP53-independent manner (3). Bond et al. (4,5) described a functional single-nucleotide polymorphism (SNP) (rs2279744) in the MDM2 gene, referred to as SNP309, with a base change from T to G. The SNP is located 309 bp downstream from intron 1 in the promoter of MDM2. This promoter is utilized by both the TP53 and RAS pathways to activate MDM2 transcription (6,7). Bond et al. (4) showed that the GG genotype of SNP309 increased the affinity of the transcription factor Sp1 to the MDM2 promoter in cell lines and that the expression of MDM2 RNA and protein was enhanced, resulting in a possible attenuation of the TP53 stress response. Functional studies with the same cell lines found transcriptionally inactive TP53–MDM2 complex and an inhibited oscillation of both proteins in cells with GG genotype (8,9). Since the publication of the original report (4), a number of studies have explored whether SNP309 was associated with the risk or the age of onset of different types of cancer. We combined the published data for breast, colorectal and lung cancers and report summary estimates of the odds ratios (ORs).


   Materials and methods
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 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary material
 Funding
 References
 
With the search term ‘MDM2 polymorphism OR MDM2 SNP’, we found 53 references in the PubMed database that were published after the first report on SNP309 (4) (last update: 13 June 2007). From these references, 36 were association studies on SNP309 with a unique sample set. A Korean sample set was reported in two publications (10,11). Table I shows the adjusted ORs with 95% confidence intervals (CIs) and P values as reported in the original papers. In these papers, the adjusted ORs compared different groups of genotypes (e.g. GG versus GT + TT or GG versus TT, etc.). Therefore, the published genotype–disease distributions were used to calculate the crude ORs for GG versus GT + TT individuals (see supplementary Table 1, available at Carcinogenesis Online). The crude ORs were combined for each of breast, colorectal and lung cancers. The Pearson statistic {lambda} was used to analyze the conditional dependence between the study and genotype given affection status. Model selection was based on likelihood ratio tests. Assessment of the association between genotypes and phenotypes was based on overall {chi}2 tests and logistic regression.


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  		Table I. Summary of studies investigating the association of MDM2 SNP309 in different cancers

 
Since all lung cancer studies reported the adjusted OR for GG versus TT, a meta-analysis was feasible. The I2 statistic was used to assess the heterogeneity of the estimated ORs among lung cancer studies. For a detailed description on the derivation and properties of this statistic, see Higgins and Thompson (2002) (12). Shortly, I2 can be interpreted as the proportion of total variation in the estimates that is due to heterogeneity between studies. Its value was derived from the logarithms of the reported ORs with 95% CIs. For the combined OR of lung cancers, 95% CIs were based on a model which included the study number as a fixed effect (supplementary Table 2 is available at Carcinogenesis Online).

Heterogeneity of the frequencies of the allele G within and between different ethnic groups was assessed by {chi}2 tests with continuity corrections as necessary. Summary CIs for the frequency of G were based on the binomial distribution (supplementary Table 4 is available at Carcinogenesis Online). The statistical analyses were conducted by using SAS software (SAS Institute, Cary, NC).


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary material
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 References
 
SNP309 and cancer risk
A summary of the 36 studies on SNP309 is given in Table I. The most frequently investigated cancer site was the breast, with 11 studies (13–22). None of them, including three studies on familial breast cancer, found SNP309 to be associated with breast cancer risk. The same was true for colorectal cancer studies (23–28). There were six case–control studies on lung cancer. Lind et al. (29) found GG to be significantly associated with lung cancer risk in non-small cell lung carcinoma. Zhang et al. (30) found GG to be associated with all analyzed subtypes of lung cancer (476 squamous cell carcinomas, 361 adenocarcinomas and 269 other subtypes). Park et al. and Jun et al. found GG to be associated with cancer risk only in non-small cell lung carcinoma and adenocarcinoma (10, 11). In a large study with 1026 cases, Li et al. (31) found the G allele to be significantly protective. In other case–control studies, no effect was found (32, 33). On other cancers, individual studies have been published (34–42) (Table I).

The crude ORs based on the genotype–disease distributions and the combined estimates for the three common cancer types (breast, colorectal and lung) are shown in Figure 1. Since they are crude ORs, they might differ from the adjusted ORs given in Table I. The combined data from 5737 breast cancer cases and 6703 controls showed no association of the SNP309 variant and cancer risk (overall {chi}2 = 0.34, P = 0.558). Neither did the combined analysis of the 1620 colorectal cancer cases and 886 controls show any genetic effect (overall {chi}2 = 0.62, P = 0.734). The combined analysis of the 4276 cases of lung cancer and the 5318 controls resulted in a significant association ({chi}2 = 10.16, P = 0.006). The summary estimates based on the crude ORs were 1.20 (95% CI = 1.06–1.35) for GG versus TT and 1.03 (95% CI = 0.93–1.13) for TG versus TT. The estimated crude OR for GG versus other genotypes was 1.18 (95% CI = 1.06–1.31). These results, together with a likelihood ratio test ({chi}2 = 0.27, P = 0.606), support a recessive penetrance for the G allele.


Figure 1
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  		Fig. 1. Relationship between SNP309 genotype and cancer risk. Crude ORs and 95% CIs were based on the reported genotype–disease distributions. ORs are logarithmically scaled. The studies are sorted by the number of included cases (with more cases towards the bottom). The genotype–phenotype distributions were combined for each cancer and the summary ORs are indicated as ‘X’. The references and the number of cases are given in the left part of the figure.

 
For lung cancer, we performed a meta-analysis based on the adjusted ORs reported for GG versus TT in seven studies. The combined estimate of the OR for the meta-analysis was OR = 1.27 (95% CI = 1.12–1.44). The estimated variability among ORs attributable to inter-study variation was 72% (95% CI = 39.5–87.1%), the remaining variation was due to variation within studies. Detailed information on subgroups of these studies can be found in supplementary Table 2 (available at Carcinogenesis Online).

Concerning the frequency of the G allele, the three African-American studies showed homogeneous frequencies (P = 0.358) with an averaged value of 10.9% (95% CI = 9.6–12.2%) (supplementary Table 4 is available at Carcinogenesis Online). The frequency of G in the Ashkenazi study was 48.5% (95% CI = 46.2–50.7%). The Caucasian studies showed heterogeneous frequencies ({chi}2 = 28.3, P = 0.042) mainly due to the outlying results from the study of Alazzouzi et al. (28). The average frequency of G in Caucasians was 36.7% (95% CI = 36.0–37.5%). The frequencies in the four Chinese studies were heterogeneous ({chi}2 = 8.87, P = 0.031) and had an average frequency of 48.4% (95% CI = 47.2–49.6%). The mean frequency of G in two Japanese studies was 49.3% (95% CI = 46.6–51.9%) and it was 53.4% (95% CI = 50.5–56.2%) in the Korean study. For detailed data, see supplementary Tables 3 and 4 (available at Carcinogenesis Online).

SNP309 and time of cancer onset
SNP309 has been shown to accelerate tumor formation in patients with Li–Fraumeni syndrome, of which the majority harbor a TP53 germ line mutation (4,44,45). SNP309 was not associated with an earlier onset of breast cancer in any of the seven case–control studies (Table I). However, two reports suggest the estrogen or progesterone receptor status to be a modifier of SNP309 susceptibility in early-onset breast cancer (13,18). The G allele of SNP309 was reported to be associated with an early onset of colorectal cancer (23,24,27) and acute lymphoblastic leukemia (39). The studies on colorectal cancer by Bond et al. and Alhopuro et al. as well as the functional study of Harris et al. (on 113 lymphocyte cell lines) suggested female cells to be more prone to an anti-apoptotic effect of the G allele.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary material
 Funding
 References
 
A functional effect of MDM2 SNP309 was shown in cell lines (4,8,47). Association studies on Li–Fraumeni syndrome and Li–Fraumeni syndrome-like patients suggest that the G allele of SNP309 accelerates tumor formation, if it occurs in combination with a weakened tumor suppressor pathway. Accordingly, cancer risk was reported to be increased by a combined effect of SNP309 plus SNPs in TP53 (30) or TP73 (10), supporting this theory. There is also some evidence that SNP309 accelerates tumor formation in cells with an increased steroid receptor status. Possible mechanisms of the interactions between SNP309 and estrogen receptor status, environmental stress and other genetic predispositions have recently been reviewed by Bond et al. (48). Based on the huge number of 5737 breast cancer cases in our combined analysis, a risk on breast cancer for the G allele of SNP309 alone can be excluded. The combined analysis included 1243 cases of familial cancer in which an inherited susceptibility allele would be expected to be enriched (49,50). In accordance with the results on breast cancer, no association was found for 1620 colorectal cancer patients. However, we cannot exclude SNP309 to be associated with the time of tumor onset in breast or colorectal cancer.

For lung cancer with an overall set of 4276 cases, our meta-analysis revealed a small but significantly increased risk for carriers of the GG genotype (OR = 1.27, 95% CI = 1.12–1.44), suggesting that the susceptibility of SNP309 might be tissue specific. Results from Zhang et al. (30) also suggest that smoking might increase the SNP309 susceptibility. In early-stage non-small cell lung cancers, the GG genotype was also found to be associated with a worse overall survival (46). For less common cancers, most of the published data showed an increased cancer risk for individuals with the GG genotype. However, these studies were single studies on individual cancers. Further independent studies on large patient series have to be conduced to confirm these findings. All together, these data show that SNP309 alone has little or no effect on the risk of common cancers, but it might modify the time of tumor onset, especially when tumor suppressor pathways are weakened, and it might also modify the survival prognosis. The translation of even promising functional data to the risk of common human cancers appears to be frustratingly complex.


   Supplementary material
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
Funding
 References
 
Supplementary Tables 1–4 can be found at http://carcin.oxfordjournals.org/


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
References
 
European Union grand (LSHC-CT-2005-503465).


   Acknowledgments
 
Conflict of interest statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 

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Received June 28, 2007; revised August 14, 2007; accepted August 14, 2007.


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