Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

Breast Center Department of Obstetrics and Gynecology University of Munich Munich Germany

Breast Service University College London Hospital London UK

Centre for Cancer Biomarkers CCBIO Department of Clinical Science University of Bergen Bergen Norway

Centre for Tumour Biology Department Barts Cancer Institute Queen Mary University of London London UK

Department of Applied Health Research University College London London UK

Department of Gynecology and Obstetrics 1st Faculty of Medicine Charles University Prague University Hospital Bulovka Prague Czech Republic

Department of Health Sciences University of Leicester Leicester LE1 7RH UK

Department of Laboratory Medicine Division of Pathology Karolinska Institutet Stockholm Sweden

Department of Non communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London UK

Department of Obstetrics and Gynaecology Haukeland University Hospital Bergen Norway

Department of Women's and Children's Health Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

Department of Women's Cancer University College London London UK

European Translational Oncology Prevention and Screening Institute Universität Innsbruck Innsbruck Austria Hall in Tirol Austria

Gynaecologic Oncology Center Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University Prague General University Hospital Prague Prague Czech Republic

Institute for Biomedical Aging Research Universität Innsbruck Innsbruck Austria

Istituto Europeo di Oncologia IRCCS Milan Italy

University of Milano Bicocca Milan Italy

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Nat Rev Clin Oncol. 2022 Jun;19(6):363-364. doi: 10.1038/s41571-022-00622-4. PubMed

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