Impact of the MDM2 promoter polymorphisms SNP285 and SNP309 on endometrial cancer risk among caucasians.

Abstract

5092 Background: MDM2 is a key regulator of p53 and, thus, of cell cycle arrest and apoptosis. The MDM2 intronic promoter polymorphism SNP309T>G increases MDM2 expression through enhanced Sp1 transcription factor binding. Conflicting evidence has linked 309G to elevated risk and early diagnosis of different cancer forms. Recently we reported a second MDM2 promoter polymorphism SNP285G>C, located on the 309G allele (Knappskog et al, Cancer Cell 2011; doi:10.1016/j.ccr.2010.12.019). SNP285C/309G accounts for 12% of the 309G alleles in Western Europeans but is non-existent among Asians. It antagonizes the effect of SNP309G by reducing Sp1 binding and reduces the risk of breast and ovarian cancer. Here, we explored the effect of SNP309 and SNP285 on risk of endometrial cancer in a European population. Methods: We analysed SNP285 and SNP309 status in 915 Norwegian endometrial cancer patients and 2.465 healthy controls. Our primary hypothesis was to examine the effect of the SNP285C/309G haplotype on endometrial cancer risk among individuals carrying the SNP309G allele. Our secondary hypothesis was to explore the effect of SNP309G on endometrial cancer risk and explore the effect of excluding individuals harbouring the SNP285C/309G haplotype from this analysis. Results: The SNP285C/309G haplotype strongly reduces the risk of endometrial cancer among carriers of the SNP309TG genotype (OR: 0.62; CI 0.42-0.91) but not among SNP309GG homozygotes (OR: 1.47; CI 0.89-2.35). SNP309TG and GG genotype carriers revealed a moderately increased risk of endometrial cancer compared to SNP309TT homozygotes (TG: OR 1.17; CI 0.99-1.37; GG: OR 1.21; CI 0.95-1.58; TG + GG combined: OR: 1.18; CI 1.01-1.37). Removing individuals harbouring the SNP309G-counteracting SNP285C from the analysis strengthened this association (TG + GG: OR: 1.20; CI 1.03-1.41). Conclusions: MDM2 promoter haplotypes influence risk of endometrial cancer, mirroring their effect on ovarian cancer. The finding that the SNP285C/309G haplotype reduces the risk of endometrial cancer by 38% among individuals expressing SNP309TG heterozygosity (about 40% of the Caucasian population) reveals ethnic diversity with respect to endometrial cancer risk.