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Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers.

ABSTRACT: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465).The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer.Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.

SUBMITTER: Bjornslett M

PROVIDER: S-EPMC3519699 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers.

Bjørnslett Merete M Knappskog Stian S Lønning Per Eystein PE Dørum Anne A

BMC cancer 20121005

<h4>Background</h4>While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.<h4>Methods</h4>221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results ...[more]

PMID: 23039163

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Project description:BackgroundGenome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.MethodsWe constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.ResultsThe PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.ConclusionsBC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Dataset Information

Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers.

Publications

Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers.

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