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Associations between MDM2 SNP309 and SNP285C haplotypes and ovarian cancer risk in BRCA1 mutation carriers.

5030 Background: While BRCA mutation carriers possess a 20-40% lifetime risk of ovarian cancer (OC), genetic modifying factors that influence the individual phenotypic expression, remains obscure. Recently, we reported the MDM2 promoter polymorphisms SNP309T>G (enhancing MDM2 transcription) and the recently discovered SNP285G>C (reducing MDM2 transcription) to enhance versus reduce risk of sporadic OC in Caucasians (Knappskog et al. Cancer Cell 2011; doi:10.1016/j.ccr.2010.12.019). We now report the distribution of two MDM2 polymorphisms in Norwegian BRCA1 related ovarian cancer.


METHODS
Blood from 135 OC patients carrying a BRCA1 mutation were analyzed for MDM2 SNP285 and SNP309 status. Distribution of the polymorphisms was compared to 1465 sporadic OC patients and 2465 healthy controls.


RESULTS
Among healthy controls, 43% harbored the 309TT genotype, 44% were 309TG, while 12% were 309GG. In contrast, the three genotypes accounted for 37%, 50% and 12% among sporadic OC patients and 32%, 49% and 19% among BRCA1 mutated OC patients, respectively (distribution difference between the three cohorts: p < 0.001). The frequency of 309GG and 309TG was significantly increased among OC patients with BRCA1 mutations as compared to healthy controls (GG: OR 2.16; CI 1.31-3.58, TG: OR 1.51; CI 1.02-2.23, combined: OR 1.65; CI 1.14-2.39) and moderately increased as compared to sporadic OC (GG: OR 1.83; CI 1.10-3.07, TG: OR 1.15; CI 0.77-1.71, combined OR 1.28; CI 0.88-1.87). Removing individuals harboring the SNP285C from the analyses strengthened the effect of SNP309G on OC risk among BRCA1 carriers compared to healthy controls (GG + TG combined: OR 1.80; CI 1.24-2.62) and sporadic OC (GG + TG combined: OR 1.34; CI 0.92-1.96). SNP285C was found to be a risk reducing factor in BRCA1 related OC as compared to healthy controls carrying the 309G allele (OR 0.36; CI 0.15-0.90).


CONCLUSIONS
The MDM2 SNP309G increases while the SNP285C reduces the risk of OC development in BRCA1 mutations carriers, resembling their effects on risk of sporadic OC. The finding that SNP285C has a counteracting effect on SNP309G may have implications for genetic counseling with respect to prophylactic risk-reducing oophorectomy in BRCA1 carriers.