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    Original Investigation
    July 1, 2020

    Association of a Polygenic Risk Score With Breast Cancer Among Women Carriers of High- and Moderate-Risk Breast Cancer Genes

    Author Affiliations
    • 1Myriad Genetics Inc, Salt Lake City, Utah
    • 2Department of Medicine, Stanford University, Palo Alto, California
    • 3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 4Dana-Farber Cancer Institute, Boston, Massachusetts
    • 5Regeneron Pharmaceuticals Inc, Tarrytown, New York
    • 6City of Hope Comprehensive Cancer Center, Duarte, California
    • 7Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    JAMA Netw Open. 2020;3(7):e208501. doi:10.1001/jamanetworkopen.2020.8501
    Key Points español 中文 (chinese)

    Question  Are polygenic risk scores associated with changes in breast cancer risks for individuals with a pathogenic variant in moderate-risk breast cancer genes?

    Findings  In this case-control study of 9802 women carrying pathogenic variants of breast cancer genes, an 86–single-nucleotide variation score was associated with breast cancer risk in each of the tested carrier populations. Stratification was more pronounced for noncarriers and CHEK2 pathogenic variant carriers than for BRCA1 or BRCA2 pathogenic variant carriers, with ATM and PALB2 pathogenic variant carriers being intermediate between those groups.

    Meaning  Theses findings suggest that the 86–single-nucleotide variation score may modify risk for carriers of BRCA1, BRCA2, CHEK2, ATM, and PALB2 pathogenic variants.


    Importance  To date, few studies have examined the extent to which polygenic single-nucleotide variation (SNV) (formerly single-nucleotide polymorphism) scores modify risk for carriers of pathogenic variants (PVs) in breast cancer susceptibility genes. In previous reports, polygenic risk modification was reduced for BRCA1 and BRCA2 PV carriers compared with noncarriers, but limited information is available for carriers of CHEK2, ATM, or PALB2 PVs.

    Objective  To examine an 86-SNV polygenic risk score (PRS) for BRCA1, BRCA2, CHEK2, ATM, and PALB2 PV carriers.

    Design, Setting, and Participants  A retrospective case-control study using data on 150 962 women tested with a multigene hereditary cancer panel between July 19, 2016, and January 11, 2019, was conducted in a commercial testing laboratory. Participants included women of European ancestry between the ages of 18 and 84 years.

    Main Outcomes and Measures  Multivariable logistic regression was used to examine the association of the 86-SNV score with invasive breast cancer after adjusting for age, ancestry, and personal and/or family cancer history. Effect sizes, expressed as standardized odds ratios (ORs) with 95% CIs, were assessed for carriers of PVs in each gene as well as for noncarriers.

    Results  The median age at hereditary cancer testing of the population was 48 years (range, 18-84 years); there were 141 160 noncarriers in addition to carriers of BRCA1 (n = 2249), BRCA2 (n = 2638), CHEK2 (n = 2564), ATM (n = 1445), and PALB2 (n = 906) PVs included in the analysis. The 86-SNV score was associated with breast cancer risk in each of the carrier populations (P < 1 × 10−4). Stratification was more pronounced for noncarriers (OR, 1.47; 95% CI, 1.45-1.49) and CHEK2 PV carriers (OR, 1.49; 95% CI, 1.36-1.64) than for carriers of BRCA1 (OR, 1.20; 95% CI, 1.10-1.32) or BRCA2 (OR, 1.23; 95% CI, 1.12-1.34) PVs. Odds ratios for ATM (OR, 1.37; 95% CI, 1.21-1.55) and PALB2 (OR, 1.34; 95% CI, 1.16-1.55) PV carrier populations were intermediate between those for BRCA1/2 and CHEK2 noncarriers.

    Conclusions and Relevance  In this study, the 86-SNV score was associated with modified risk for carriers of BRCA1, BRCA2, CHEK2, ATM, and PALB2 PVs. This finding supports previous reports of reduced PRS stratification for BRCA1 and BRCA2 PV carriers compared with noncarriers. Modification of risk in CHEK2 carriers associated with the 86-SNV score appeared to be similar to that observed in women without a PV. Larger studies are needed to provide more refined estimates of polygenic modification of risk for women with PVs in other moderate-penetrance genes.