To individualise breast cancer (BC) prevention, markers to follow a person's changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n = 1848) and single nucleotide polymorphisms (n = 1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC = 0.71 [95% CI: 0.65-0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7-21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification.

Breast Center Department of Obstetrics and Gynecology and CCC Munich LMU University Hospital Munich Germany

Department of Applied Health Research University College London London UK

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

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

Department of Women's Cancer UCL EGA Institute for Women's Health University College London Medical School Building Room 340 74 Huntley Street WC1E 6AU London UK

European Translational Oncology Prevention and Screening Institute Milser Str 10 6060 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

Istituto Europeo di Oncologia Milan Italy

Research Institute for Biomedical Aging Research Universität Innsbruck 6020 Innsbruck Austria

University of Milano Bicocca Milan Italy

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Systems epigenetic approach towards non-invasive breast cancer detection