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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)171-179
Number of pages9
JournalCancer Causes and Control
Volume20
Issue number2
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Fingerprint

Skin Neoplasms
Single Nucleotide Polymorphism
Genotype
Confidence Intervals
Phenotype
Case-Control Studies
Squamous Cell Carcinoma
Alleles
Odds Ratio
Nurses
Tanning
Skin Pigmentation
Oncogene Proteins
Basal Cell Carcinoma
Health
Genetic Promoter Regions
Melanoma
Genes
Neoplasms
Proteins

Keywords

  • MDM2
  • P53
  • Pigmentary phenotypes
  • Skin cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer. / Nan, Hongmei; Qureshi, Abrar A.; Hunter, David J.; Han, Jiali.

In: Cancer Causes and Control, Vol. 20, No. 2, 01.03.2009, p. 171-179.

Research output: Contribution to journalArticle

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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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