Association of a Polygenic Risk Score With Breast Cancer Among Women Carriers of High- and Moderate-Risk Breast Cancer Genes
Authors: Shannon Gallagher, Elisha Hughes, Susanne Wagner, Placede Tshiaba, Eric Rosenthal, Benjamin B. Roa, Allison W. Kurian, Susan M. Domchek, Judy Garber, Johnathan Lancaster, Jeffrey N. Weitzel, Alexander Gutin, Jerry S. Lanchbury, Mark Robson
Journal: JAMA Network Open (2020)

<h3>Importance</h3> 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<i>BRCA1</i>and<i>BRCA2</i>PV carriers compared with noncarriers, but limited information is available for carriers of<i>CHEK2</i>,<i>ATM</i>, or<i>PALB2</i>PVs. <h3>Objective</h3> To examine an 86-SNV polygenic risk score (PRS) for<i>BRCA1</i>,<i>BRCA2</i>,<i>CHEK2</i>,<i>ATM</i>, and<i>PALB2</i>PV carriers. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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<i>BRCA1</i>(n = 2249),<i>BRCA2</i>(n = 2638),<i>CHEK2</i>(n = 2564),<i>ATM</i>(n = 1445), and<i>PALB2</i>(n = 906) PVs included in the analysis. The 86-SNV score was associated with breast cancer risk in each of the carrier populations (<i>P</i> &lt; 1 × 10<sup>−4</sup>). Stratification was more pronounced for noncarriers (OR, 1.47; 95% CI, 1.45-1.49) and<i>CHEK2</i>PV carriers (OR, 1.49; 95% CI, 1.36-1.64) than for carriers of<i>BRCA1</i>(OR, 1.20; 95% CI, 1.10-1.32) or<i>BRCA2</i>(OR, 1.23; 95% CI, 1.12-1.34) PVs. Odds ratios for<i>ATM</i>(OR, 1.37; 95% CI, 1.21-1.55) and<i>PALB2</i>(OR, 1.34; 95% CI, 1.16-1.55) PV carrier populations were intermediate between those for<i>BRCA1</i>/<i>2</i>and<i>CHEK2</i>noncarriers. <h3>Conclusions and Relevance</h3> In this study, the 86-SNV score was associated with modified risk for carriers of<i>BRCA1</i>,<i>BRCA2</i>,<i>CHEK2</i>,<i>ATM</i>, and<i>PALB2</i>PVs. This finding supports previous reports of reduced PRS stratification for<i>BRCA1</i>and<i>BRCA2</i>PV carriers compared with noncarriers. Modification of risk in<i>CHEK2</i>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.