Combining rare and common genetic variants improves population risk stratification for breast cancer

Abstract

AbstractPurposeIn the United States, breast cancer clinical risk assessments are inconsistent and inequitable. The previous success ofBRCA1andBRCA2screening has demonstrated that genetics could be used to reduce these inequities, if they are available and accessible across the population. The aim of this study is to evaluate the performance of different genetic screening approaches to identify women at high-risk of breast cancer in the general population.MethodsWe did a retrospective study on 25,591 women participating in the Healthy Nevada Project. Electronic Health Records (EHR) data were used to identify women with a family history of, and women who were diagnosed with breast cancer. The genetic analysis assessed the role of rare predicted loss-of-function (pLOF) variants inBRCA1,BRCA2,PALB2,ATMandCHEK2, as well as the combined role of common variants via a polygenic risk score. Women were considered at high-risk of breast cancer if they had greater than 20% probability of being diagnosed with breast cancer by age 70.ResultsFamily history of breast cancer (FHx-BrCa) was ascertained on or after the record of breast cancer for 78% of women with both, indicating that this method for risk assessment is not being properly utilized for early screening. Genetics offered an alternative method for risk assessment. 11.4% of women in HNP were at high-risk of breast cancer based on their genetic risk: having a pLOF variant inBRCA1,BRCA2orPALB2(hazard ratio = 10.4, 95% confidence interval: 8.1-13.5), or a pLOF variant inATMorCHEK2(HR = 3.4, CI: 2.4-4.8), or being in the top 10% of the polygenic risk score distribution (HR = 2.4, CI: 2.0-2.8). We also showed that combining PRS with pLOF inATMandCHEK2allowed a better identification of participants with high risk while minimizing false positives. Women with a pLOF inATMorCHEK2and in the top 50% of the PRS are at high risk (39.2% probability of breast cancer at age 70), while those with a pLOF inATMorCHEK2and in the bottom 50% of the PRS are not at high risk (14.4% probability of breast cancer at age 70).ConclusionThese results suggest that a combined monogenic and polygenic approach may best capture the inherited risk for breast cancer across the population.