Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab.

Li H1, Feng B2, Miron A3,4, Chen X5, Beesley J5, Bimeh E6, Barrowdale D7, John EM8,9, Daly MB10, Andrulis IL11, Buys SS12, Kraft P13; kConFab investigators, Thorne H14, Chenevix-Trench G5, Southey MC15, Antoniou AC7, James PA16,17, Terry MB18,19, Phillips KA16,17,20, Hopper JL20, Mitchell G16,17, Goldgar DE1,2.

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Abstract

PURPOSE:

This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).

METHODS:

We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.

RESULTS:

The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10-6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.

CONCLUSION:

Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med advance online publication 12 May 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.43.