A steroid metabolizing gene variant in a polyfactorial model improves risk prediction in a high incidence breast cancer population

• A polyfactorial breast cancer risk assessment model (PFRM) was built and validated.
• The optimized PFRM incorporates both genetic (22 SNPs/19 genes) and clinical risk factors.
• The PFRM was further validated in a high risk USA/Marin breast cancer population.
• This PFRM consistently performed significantly better than the BCRAT (Gail model).
• A functional aldosterone synthase SNP in PFRM improved predictive performance in Marin.

BackgroundWe have combined functional gene polymorphisms with clinical factors to improve prediction and understanding of sporadic breast cancer risk, particularly within a high incidence Caucasian population.MethodsA polyfactorial risk model (PFRM) was built from both clinical data and functional single nucleotide polymorphism (SNP) gene candidates using multivariate logistic regression analysis on data from 5022 US Caucasian females (1671 breast cancer cases, 3351 controls), validated in an independent set of 1193 women (400 cases, 793 controls), and reassessed in a unique high incidence breast cancer population (165 cases, 173 controls) from Marin County, CA.ResultsThe optimized PFRM consisted of 22 SNPs (19 genes, 6 regulating steroid metabolism) and 5 clinical risk factors, and its 5-year and lifetime risk prediction performance proved significantly superior (~ 2-fold) over the Gail model (Breast Cancer Risk Assessment Tool, BCRAT), whether assessed by odds (OR) or positive likelihood (PLR) ratios over increasing model risk levels. Improved performance of the PFRM in high risk Marin women was due in part to genotype enrichment by a CYP11B2 (-344T/C) variant.Conclusions and general significanceSince the optimized PFRM consistently outperformed BCRAT in all Caucasian study populations, it represents an improved personalized risk assessment tool. The finding of higher Marin County risk linked to a CYP11B2 aldosterone synthase SNP associated with essential hypertension offers a new genetic clue to sporadic breast cancer predisposition.