PURPOSE: MDM2 is believed to regulate the p53 level in modulating DNA repair, cell cycle control, cell growth, and apoptosis. We hypothesize that genetic variants in the MDM2 gene are associated with risk of bladder cancer. EXPERIMENTAL DESIGN: We first conducted a case-control study of 234 bladder cancer cases and 253 cancer-free controls, using the haplotype-based tagging single nucleotide polymorphism (SNP) approach involving 13 common SNPs initially identified in 100 control subjects. We then examined the functionality of the important SNP. RESULTS: We found that the C1797G polymorphism in the MDM2 promoter region is an important SNP because its homozygous variant genotype, but none of the haplotypes, was associated with risk of bladder cancer. Electrophoretic mobility shift assay indicated that the 1797C to 1797G transition within the CAAT/enhancer binding protein alpha (C/EBP alpha) core sequence greatly enhanced the C/EBP alpha binding affinity to the promoter region. The in vitro luciferase assays in various cell lines further showed an increased transcriptional activity of the 1797G allele compared with the 1797C allele. Additional experiments with tumor tissues revealed that the transcriptional activator C/EBP alpha containing the 1797G allele increased levels of the MDM2 mRNA and protein in bladder tumor tissues. CONCLUSIONS: These data suggested that the novel MDM2 promoter C1797G polymorphism may affect the MDM2 activity by altering the C/EBP alpha binding affinity to the promoter and, thus, may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Further validation of the functionality of the MDM2 C1797G polymorphism and its association with risk of bladder and other cancers in other ethnic populations is warranted.
PURPOSE:MDM2 is believed to regulate the p53 level in modulating DNA repair, cell cycle control, cell growth, and apoptosis. We hypothesize that genetic variants in the MDM2 gene are associated with risk of bladder cancer. EXPERIMENTAL DESIGN: We first conducted a case-control study of 234 bladder cancer cases and 253 cancer-free controls, using the haplotype-based tagging single nucleotide polymorphism (SNP) approach involving 13 common SNPs initially identified in 100 control subjects. We then examined the functionality of the important SNP. RESULTS: We found that the C1797G polymorphism in the MDM2 promoter region is an important SNP because its homozygous variant genotype, but none of the haplotypes, was associated with risk of bladder cancer. Electrophoretic mobility shift assay indicated that the 1797C to 1797G transition within the CAAT/enhancer binding protein alpha (C/EBP alpha) core sequence greatly enhanced the C/EBP alpha binding affinity to the promoter region. The in vitro luciferase assays in various cell lines further showed an increased transcriptional activity of the 1797G allele compared with the 1797C allele. Additional experiments with tumor tissues revealed that the transcriptional activator C/EBP alpha containing the 1797G allele increased levels of the MDM2 mRNA and protein in bladder tumor tissues. CONCLUSIONS: These data suggested that the novel MDM2 promoter C1797G polymorphism may affect the MDM2 activity by altering the C/EBP alpha binding affinity to the promoter and, thus, may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Further validation of the functionality of the MDM2C1797G polymorphism and its association with risk of bladder and other cancers in other ethnic populations is warranted.