Abstract P4-12-05: Enrichment of aldosterone synthase (CYP11B2) gene C-allele carriers in women at high risk in the OncoVue® polyfactorial risk model

Abstract

Abstract Background: Models for accurately assessing breast cancer risk are utilized for guiding clinical decisions regarding early detection and prevention. We developed a polyfactorial risk model (PFRM; OncoVue) from analysis of a large case-control database including both functional gene polymorphism and clinical factor data. A multivariate logistic regression based statistical protocol was used to derive a single risk model consisting of 22 single nucleotide polymorphisms (SNPs) in 19 genes and 5 traditional risk factors. Several studies have shown that the PFRM is significantly improved in individualized risk estimation compared to the Breast Cancer Risk Assessment Tool (BCRAT) or Gail model. Here we have examined the genotype frequencies of women placed in the highest decile of risk by the PFRM compared to both the overall control population and to women in the control population placed at the lowest decile of risk. Materials and Methods: Analyses were performed on 1671 breast cancer cases and 3351 controls that enrolled in a case-control study conducted in six regions of the United States. DNAs were genotyped for the 22 genetic polymorphisms and combined with clinical risk factor information to calculate PFRM risk estimates for the individual participants. The PFRM lifetime scores were used to stratify the upper and lower deciles of risk. The genotype frequencies for these stratified risk groups were determined and compared to the overall control population and to each other (upper vs. lower decile). Odds Ratios (OR) were determined for the CYP11B2 genotypes because they exhibited the largest differences in frequency among the groups. Results: For CYP11B2 comparison of the genotype frequencies in the highest decile risk group to the overall genotype frequencies of controls identified significant enrichment of the C-allele carriers in the highest risk group. The OR for C-allele carriers (C/C+C/T) compared to the most common T/T genotype was 3.0 (1.9, 4.8; 95% C.I.) with a p-value <0.0001. Similarly for the upper decile risk group compared to the lower decile risk group the association of C-allele carriers was even stronger with OR = 11.0 (6.6,18.4; p <0.0001). In the upper decile of risk 86% of the individuals were C-allele carriers compared to only 38% in the lower decile of risk. Conclusions: Our previous studies have shown an age dependent association of the CYP11B2 C/C and C/T genotypes with breast cancer risk. The enrichment of these genotypes in women in the upper decile risk group as determined by the PFRM further reinforces the role of this genotype in influencing breast cancer risk and suggests that intervention in the aldosterone synthase pathway be explored as a method of breast cancer prevention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-05.