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. 2020 Jul 1;3(7):e208501.
doi: 10.1001/jamanetworkopen.2020.8501.

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

Shannon Gallagher  1 , Elisha Hughes  1 , Susanne Wagner  1 , Placede Tshiaba  1 , Eric Rosenthal  1 , Benjamin B Roa  1 , Allison W Kurian  2 , Susan M Domchek  3 , Judy Garber  4 , Johnathan Lancaster  1   5 , Jeffrey N Weitzel  6 , Alexander Gutin  1 , Jerry S Lanchbury  1 , Mark Robson  7
Affiliations

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

Shannon Gallagher et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Gallagher reported receiving personal fees from Myriad Genetics Inc during the conduct of the study. Dr Hughes reported receiving personal fees from Myriad Genetics Inc during the conduct of the study. Dr Wagner reported receiving salary and restricted stock from Myriad Genetics Inc. Ms Tshiaba reported receiving personal fees from Myriad Genetics Inc during the conduct of the study. Dr Rosenthal reported receiving personal fees from Myriad Genetics during the conduct of the study. Dr Kurian reported receiving grants from Myriad Genetics outside the submitted work. Dr Domchek reported receiving personal fees from AstraZeneca, BMS, and Clovis outside the submitted work and research funding for clinical trials provided to the University of Pennsylvania from Clovis, AstraZeneca, and Pharmamar. Dr Garber reported serving as an uncompensated advisory board member for Konica-Minolta and receiving research support from Ambry, Invitae, and Myriad outside the submitted work. Dr Lancaster reported being a previous employee of Myriad Genetics and a current employee of Regeneron Pharmaceuticals. Dr Gutin reported being an employee of Myriad Genetics Inc and owning Myriad Genetics Inc stock. Dr Robson reported receiving nonfinancial support from Invitae outside the submitted work and honoraria from AstraZeneca; uncompensated consulting or advisory positions for AstraZeneca, Change Healthcare Daiichi-Sankyo, Epic Sciences, Merck, and Pfizer; research funding to Memorial Sloan Kettering Cancer Center from AbbVie, AstraZeneca, Merck, Pfizer, and Tesaro; travel, accommodation, and expenses reimbursement from AstraZeneca and Merck; compensation for editorial services from AstraZeneca and Pfizer; and grant P30 CA008748 from the National Institutes of Health/National Cancer Institute. No other disclosures were reported.

Figures

Figure.
Figure.. Modification of Lifetime Breast Cancer Risk for Pathogenic Variant Carriers and Noncarriers by an 86–Single-Nucleotide Variant Score
Probability density function against absolute risk estimates by age 80 years, shaded by gene with a pathogenic variant. Baseline gene-specific risk was calculated from Lee et al., Baseline risk for noncarriers was obtained using Surveillance, Epidemiology, and End Results 2013 to 2015 lifetime risk data for individuals with white racial ancestry.
See this image and copyright information in PMC

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