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

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.

SUBMITTER: Nan H

PROVIDER: S-EPMC2631619 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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

Nan Hongmei H Qureshi Abrar A AA Hunter David J DJ Han Jiali J

Cancer causes & control : CCC 20080924 2

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 evaluat ...[more]

PMID: 18814047

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Project description:Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. We evaluated the associations between 15 SNPs in 8 candidate pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP and ATRN) and both pigmentary phenotypes (hair color, skin color and tanning ability) and skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases and 870 common controls. We found that the TYR Arg402Gln variant was significantly associated with skin color (p-value = 7.7 x 10(-4)) and tanning ability (p-value = 7.3 x 10(-4)); the SLC45A2 Phe374Leu variant was significantly associated with hair color (black to blonde) (p-value = 2.4 x 10(-7)), skin color (p-value = 1.1 x 10(-7)) and tanning ability (p-value = 2.5 x 10(-4)). These associations remained significant after controlling for MC1R variants. No significant associations were found between these polymorphisms and the risk of skin cancer. We observed that the TYRP1 rs1408799 and SLC45A2 1721 C>G were associated with melanoma risk (OR, 0.77; 95% CI, 0.60-0.98 and OR, 0.75; 95% CI, 0.60-0.95, respectively). The TYR Ser192Tyr was associated with SCC risk (OR, 1.23; 95% CI, 1.00-1.50). The TYR haplotype carrying only the Arg402Gln variant allele was significantly associated with SCC risk (OR, 1.35; 95% CI, 1.04-1.74). The OCA2 Arg419Gln and ASIP g.8818 A>G were associated with BCC risk (OR, 1.50; 95% CI, 1.06-2.13 and OR, 0.73; 95% CI, 0.53-1.00, respectively). The haplotype near ASIP (rs4911414[T] and rs1015362[G]) was significantly associated with fair skin color (OR, 2.28; 95% CI, 1.46-3.57) as well as the risks of melanoma (OR, 1.68; 95% CI, 1.18-2.39) and SCC (OR, 1.54; 95% CI, 1.08-2.19). These associations remained similar after adjusting for pigmentary phenotypes and MC1R variants. The statistical power of our study was modest and additional studies are warranted to confirm the associations observed in the present study. Our study provides evidence for the contribution of pigmentation genetic variants, in addition to the MC1R variants, to variation in human pigmentary phenotypes and possibly the development of skin cancer.

Dataset Information

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

Publications

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

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