Evidence of Accelerated Epigenetic Aging of Breast Tissues In Patients With Breast Cancer Is Driven By CpGs Associated With Polycomb Related Genes

Abstract Purpose: Age is one of the strongest risk factors for the development of breast cancer, however the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results: The Levine (p=0.0037) and Yang clocks (p=0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p=0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb related genes can be used to assess the risk of developing breast cancer among unaffected individuals.