Polygenic prediction of breast cancer: comparison of genetic predictors and implications for risk stratification

Published genetic risk scores for breast cancer (BC) so far have been based on a relatively small number of markers and are not necessarily using the full potential of large-scale Genome-Wide Association Studies. This study aimed to identify an efficient polygenic predictor for BC based on best available evidence and to assess its potential for personalized risk prediction and screening strategies.

Four different genetic risk scores (two already published and two newly developed) and their combinations (metaGRS) were compared in the subsets of two population-based biobank cohorts: the UK Biobank (UKBB, 3157 BC cases, 43,827 controls) and Estonian Biobank (EstBB, 317 prevalent and 308 incident BC cases in 32,557 women). In addition, correlations between different genetic risk scores and their associations with BC risk factors were studied in both cohorts.

The metaGRS that combines two genetic risk scores (metaGRS₂ - based on 75 and 898 Single Nucleotide Polymorphisms, respectively) had the strongest association with prevalent BC status in both cohorts. One standard deviation difference in the metaGRS₂ corresponded to an Odds Ratio = 1.6 (95% CI 1.54 to 1.66, p = 9.7*10^- 135) in the UK Biobank and accounting for family history marginally attenuated the effect (Odds Ratio = 1.58, 95% CI 1.53 to 1.64, p = 7.8*10^- 129). In the EstBB cohort, the hazard ratio of incident BC for the women in the top 5% of the metaGRS₂ compared to women in the lowest 50% was 4.2 (95% CI 2.8 to 6.2, p = 8.1*10^- 13). The different GRSs were only moderately correlated with each other and were associated with different known predictors of BC. The classification of genetic risk for the same individual varied considerably depending on the chosen GRS.

We have shown that metaGRS_2, that combined on the effects of more than 900 SNPs, provided best predictive ability for breast cancer in two different population-based cohorts. The strength of the effect of metaGRS₂ indicates that the GRS could potentially be used to develop more efficient strategies for breast cancer screening for genotyped women.