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A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer

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Abstract

The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein’s transcriptional activity. We evaluated the effect of MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case–control study within the Nurses’ Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3,207 women pooled from controls of three nested case–control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78–1.08) and 0.68 (95% CI, 0.53–0.87), respectively (p, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01–1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wild-type group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits.

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Abbreviations

BCC:

Basal cell carcinoma

SCC:

Squamous cell carcinoma

CI:

Confidence interval

OR:

Odds ratio

UV:

Ultraviolet

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Acknowledgments

We thank Ms. Qun Guo for her programming support. We are indebted to the participants in the Nurses’ Health Study for their dedication and commitment.

Grant sponsor

NIH; Grant number: CA128080 and CA122838.

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Authors and Affiliations

  1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA

    Hongmei Nan, David J. Hunter & Jiali Han

  2. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Hongmei Nan & David J. Hunter

  3. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Hongmei Nan, Abrar A. Qureshi, David J. Hunter & Jiali Han

  4. Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Abrar A. Qureshi

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  1. Hongmei Nan
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Correspondence to Hongmei Nan.

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Nan, H., Qureshi, A.A., Hunter, D.J. et al. A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer. Cancer Causes Control 20, 171–179 (2009). https://doi.org/10.1007/s10552-008-9231-9

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  • DOI: https://doi.org/10.1007/s10552-008-9231-9

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