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Abstract
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.
Highlights
Genetic and non-genetic factors contribute to breast cancer development
We assessed the level of cell-type heterogeneity in each cervical sample using EpiDISH26, an algorithm that infers the relative proportion of epithelial cells, fibroblasts, and seven subtypes of immune cells in each sample
We have identified a cervical DNAme signature, the WID-BC-index, which provides an opportunity to identify women with a poor prognostic primary breast cancer based on a sample, which has no direct anatomical link to the diseased organ
Summary
Genetic and non-genetic factors contribute to breast cancer development. An epigenomebased signature capturing these components in accessible samples could identify women at risk. 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. Epigenetic (i.e. DNAme) changes have been identified in normal breast tissue adjacent to breast cancers[9] and could potentially serve as a surrogate for both genetic and non-genetic factors including lifestyle, reproductive and environmental exposures contributing to breast cancer development[10]. We aimed to assess whether DNAme profiles derived from cervical liquid-based cytology samples (i.e. containing hormone-sensitive epithelial cells, which are capable of recording breast cancer-predisposing factors at the level of the epigenome[24] and can be self-collected), are able to identify women with primary breast cancer. We assess DNAme at progesterone receptor binding sites (PR-BS) in breast and cervical samples to evaluate whether systemic factors driving carcinogenesis in the breast can be captured by assessment of the cervical epigenome
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