Polygenic risk scores stratify breast cancer risk among women with benign breast disease

Mark E Sherman¹, Stacey J Winham², Robert A Vierkant², Bryan M McCauley², Christopher G Scott², Sarah Schrup³, Mia M Gaudet⁴, Melissa A Troester^{5

6}, Sandhya Pruthi⁷, Derek C Radisky⁸, Amy C Degnim⁹, Fergus J Couch¹⁰, Manjeet K Bolla¹¹, Qin Wang¹¹, Joe Dennis¹¹, Kyriaki Michailidou^{11

12}, Pascal Guenel¹³, Therese Truong¹³, Jenny Chang-Claude^{14

15}, Nadia Obi^{16

17}, Kristan J Aronson¹⁸, Rachel Murphy¹⁹, Montserrat Garcia-Closas²⁰, Stephen Chanock²⁰, Thomas Ahearn²⁰, Xiaohong Yang²⁰, Alison M Dunning²¹, Nasim Mavaddat¹¹, Paul D P Pharoah¹¹, Douglas F Easton¹¹, Celine M Vachon²

Affiliations

¹ Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, United States.
² Department of Quantitative Health Sciences, Mayo Clinic, Rocheseter, MN 55905, United States.
³ Mayo Clinic Alix School of Medicine, Rochester, MN 55905, United States.
⁴ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, United States.
⁵ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
⁶ Department of Epidemiology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.
⁷ Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States.
⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States.
⁹ Department of Surgery, Mayo Clinic, Rochester, MN 55905, United States.
¹⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1 TN, United Kingdom.
¹² Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus.
¹³ Cancer and Environment Group, Center for Research in Epidemiology and Population Health, University Paris-Sud, University Paris-Saclay, Villejuif 94807, France.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.
¹⁵ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁶ Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁷ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁸ Departments of Public Health Sciences and Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
¹⁹ School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
²⁰ Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
²¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, United Kingdom.

PMID: 39412492
PMCID: PMC11884851 (available on 2025-10-16)
DOI: 10.1093/jnci/djae255

Polygenic risk scores stratify breast cancer risk among women with benign breast disease

Mark E Sherman et al. J Natl Cancer Inst. 2025.

. 2025 Mar 1;117(3):456-464.

doi: 10.1093/jnci/djae255.

Authors

Affiliations

¹ Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, United States.
² Department of Quantitative Health Sciences, Mayo Clinic, Rocheseter, MN 55905, United States.
³ Mayo Clinic Alix School of Medicine, Rochester, MN 55905, United States.
⁴ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, United States.
⁵ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
⁶ Department of Epidemiology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.
⁷ Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States.
⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States.
⁹ Department of Surgery, Mayo Clinic, Rochester, MN 55905, United States.
¹⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1 TN, United Kingdom.
¹² Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus.
¹³ Cancer and Environment Group, Center for Research in Epidemiology and Population Health, University Paris-Sud, University Paris-Saclay, Villejuif 94807, France.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.
¹⁵ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁶ Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁷ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
¹⁸ Departments of Public Health Sciences and Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
¹⁹ School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
²⁰ Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
²¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, United Kingdom.

PMID: 39412492
PMCID: PMC11884851 (available on 2025-10-16)
DOI: 10.1093/jnci/djae255

Abstract

Background: Most breast biopsies are diagnosed as benign breast disease, with 1.5- to 4-fold increased breast cancer risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in breast cancer risk assessment of these patients. We assessed whether a 313-single nucleotide variation (formerly single-nucleotide polymorphism) polygenic risk score stratifies risk of benign breast disease patients.

Methods: We pooled data from 5 Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6706 participants with breast cancer and 8488 participants without breast cancer. Using logistic regression, we estimated breast cancer risk associations by self-reported benign breast disease history and strata of polygenic risk score, with median polygenic risk score category among women without benign breast disease as the referent. We assessed interactions and mediation of benign breast disease and polygenic risk score with breast cancer risk.

Results: Benign breast disease history was associated with increased breast cancer risk (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.37 to 1.60; P < .001). Polygenic risk score increased breast cancer risk, irrespective of benign breast disease history (Pinteraction = .48), with minimal evidence of mediation of either factor by the other. Women with benign breast disease and polygenic risk score in the highest tertile had more than twofold increased odds of breast cancer (OR = 2.73, 95% CI = 2.41 to 3.09), and those with benign breast disease and polygenic risk score in the lowest tertile experienced reduced breast cancer risk (OR = 0.79, 95% CI = 0.70 to 0.91) compared with the referent group. Women with benign breast disease and polygenic risk score in the highest decile had a 3.7-fold increase (95% CI = 3.00 to 4.61) compared with those with median polygenic risk score without benign breast disease.

Conclusion: Breast cancer risks are elevated among women with benign breast disease and increase progressively with polygenic risk score, suggesting that optimal combinations of these factors may improve risk stratification.

© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

None declared.

References

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Polygenic risk scores stratify breast cancer risk among women with benign breast disease

Affiliations

Polygenic risk scores stratify breast cancer risk among women with benign breast disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical