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

Mark E Sherman; Stacey J Winham; Robert A Vierkant; Bryan M Mccauley; Christopher G Scott; Sarah Schrup; Mia M Gaudet; Melissa A Troester; Sandhya Pruthi; Derek C Radisky; Amy C Degnim; Fergus J Couch; Manjeet K Bolla; Qin Wang; Joe Dennis; Kyriaki Michailidou; Pascal Guenel; Therese Truong; Jenny Chang-Claude; Nadia Obi; Kristan J Aronson; Rachel Murphy; Montserrat Garcia-Closas; Stephen Chanock; Thomas Ahearn; Xiaohong Yang; Alison M Dunning; Nasim Mavaddat; Paul D P Pharoah; Douglas F Easton; Celine M Vachon

doi:10.1093/jnci/djae255

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

J Natl Cancer Inst. 2024 Oct 16:djae255. doi: 10.1093/jnci/djae255. Online ahead of print.

Authors

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, USA.
² Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA, and Rochester, MN, USA.
³ Mayo Clinic Alix School of Medicine, Rochester, MN, USA.
⁴ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁵ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
⁷ Department of Medicine, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
⁹ Department of Surgery, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
¹² Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, 1683, Cyprus.
¹³ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
¹⁵ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.
¹⁷ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁸ Department of Public Health Sciences, and Cancer Research Institute, Kingston, ON, Canada.
¹⁹ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
²⁰ Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.

PMID: 39412492
DOI: 10.1093/jnci/djae255

Abstract

Purpose: Most breast biopsies are diagnosed as benign breast disease (BBD), with 1.5- to fourfold increased breast cancer (BC) risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in BC risk assessment of these patients. We assessed whether a 313-SNP polygenic risk score (PRS) stratifies risk of BBD patients.

Patients and methods: We pooled data from five Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6,706 cases and 8,488 controls. Using logistic regression, we estimated BC risk associations by self-reported BBD history and strata of PRS, with median PRS category among women without BBD as the referent. We assessed interactions and mediation of BBD and PRS with BC risk.

Results: BBD history was associated with increased BC risk (OR = 1.48, 95% CI: 1.37-1.60; p < .001). PRS increased BC risk, irrespective of BBD history (p-interaction = 0.48), with minimal evidence of mediation of either factor by the other. Women with BBD and PRS in the highest tertile had over 2-fold increased odds of BC (OR = 2.73, 95% CI: 2.41-3.09) and those with BBD and PRS in the lowest tertile experienced reduced BC risk (OR = 0.79, 95% CI: 0.70-0.91), compared to the reference group. Women with BBD and PRS in the highest decile had a 3.7- fold increase (95% CI: 3.00-4.61) compared to those with median PRS without BBD.

Conclusion: BC risks are elevated among women with BBD and increase progressively with PRS, suggesting that optimal combinations of these factors may improve risk stratification.