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

Abstract

Purpose: This study aimed to evaluate the performance of different genetic screening approaches to identify women at high risk of breast cancer in the general population. Methods: We retrospectively studied 25,591 women with available electronic health records and genetic data, participants in the Healthy Nevada Project. Results: Family history of breast cancer was ascertained on or after the record of breast cancer for 78% of women with both, indicating that this risk assessment method is not being properly utilized for early screening. Genetics offered an alternative method for risk assessment. 11.4% of women were identified as high risk based on possessing a predicted loss-of-function (pLOF) variant in BRCA1, BRCA2, or PALB2 (hazard ratio = 10.4, 95% confidence interval: 8.1-13.5) or a pLOF variant in ATM or CHEK2 (hazard ratio = 3.4, CI: 2.4-4.8) or being in the top 10% of the polygenic risk score (PRS) distribution (hazard ratio = 2.4, CI: 2.0-2.8). Moreover, women with a pLOF in ATM or CHEK2 and ranking in the top 50% of the PRS displayed a high risk (39.2% probability of breast cancer at age 70), whereas their counterparts in the bottom 50% of the PRS were not at high risk (14.4% probability at age 70). Conclusion: Our findings suggest that a combined monogenic and polygenic approach allowed a better identification of participants with high risk while minimizing false positives.

Keywords

• ATM and CHEK2
• Breast cancer
• Family history
• Polygenic risk score
• Population screening