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Cited by 137BRCA gene mutations in cancerGenetic Associations and EpidemiologyGenetic factors in colorectal cancer

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

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Gallagher, Shannon, Hughes, Elisha, Wagner, Susanne, Tshiaba, Placede, Rosenthal, Eric, Roa, Benjamin B., Kurian, Allison W., Domchek, Susan M. +6 more·2020·JAMA Network Open
DOI 10.1001/jamanetworkopen.2020.8501PMC PMC7330720
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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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  • The importance of polygenic variation on large-effect, monogenic variants has been clearly demonstrated for rare alleles, such as for BRCA1 and BRCA2 variants that predispose to breast cancer.

    “The importance of polygenic variation on large-effect, monogenic variants has been clearly demonstrated for rare alleles, such as for the BRCA1 and BRCA2 variants that predispose to breast cancer (Fahed et al., 2019; Gallagher et al., 2020).”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Gallagher et al., 2020

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  1. [42]Rothman KJ, Greenland S, Lash T. Modern Epidemiology. Vol 3. Lippincott Williams & Wilkins; 2008.

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Authors
Gallagher, S., Hughes, E., Wagner, S., Tshiaba, P., Rosenthal, E., Roa, B. B., Kurian, A. W., Domchek, S. M., Garber, J., Lancaster, J., Weitzel, J. N., Gutin, A., Lanchbury, J. S., & Robson, M.
Affiliations
  • Myriad Genetics (US)
  • Stanford University (US)
  • University of Pennsylvania (US)
  • Dana-Farber Cancer Institute (US)
  • Regeneron (United States) (US)
  • City Of Hope National Medical Center (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Robson, Mark
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2020-07-01
Volume
3
Issue
7
Pages
e208501
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2020.8501
PMC
PMC7330720
OpenAlex
W3038986364
Cited by
137
References
42
Citations by year
2026: 13 · 2025: 23 · 2024: 24 · 2023: 14 · 2022: 23 · 2021: 33 · 2020: 7
FWCI
11.29
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • JAMA Network Open (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Myriad Genetics
  • National Cancer Institute (P30CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
polygenic risk score, breast cancer risk, BRCA1, BRCA2, CHEK2, ATM, PALB2, pathogenic variants, hereditary breast cancer, single nucleotide polymorphisms, risk factor control, European ancestry women, invasive breast cancer, risk stratification
MeSH terms
Fanconi Anemia Complementation Group N Protein, Breast Neoplasms, Female, Genetic Testing, Humans, Middle Aged, Research Design, United States, Case-Control Studies, Risk Assessment, BRCA1 Protein, Genetic Predisposition to Disease, BRCA2 Protein, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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