A new breast tissue-specific epigenetic clock (BTEC) estimates chronological age more accurately than classical clocks and reveals that breast tumors do not generally show accelerated epigenetic aging.
What was known
Epigenetic clocks estimate biological age from DNA methylation patterns across tissues, but their accuracy in breast tissue was suboptimal. Classical models such as Horvath’s and Hannum’s clocks predict chronological age poorly in breast tissue, underscoring the need for a tissue-specific approach.
What this work adds
BTEC was developed from DNA methylation data of 553 healthy breast tissue samples from seven different studies. The authors compared its performance with existing clocks and also analyzed its behavior in tumor-adjacent and tumor samples by molecular subtype. They further assessed the prognostic value of extreme epigenetic age deviations in an exploratory analysis.
Main results
BTEC outperformed existing clocks, with better correlation with chronological age (r = 0.91) and a lower mean absolute error (3.0 years), without requiring dataset-specific adjustments. It showed consistent performance across ancestry groups, unlike the classical clocks, which had variable biases. Tumor-adjacent samples showed an average deviation of -2.3 years, far greater in tumor samples (-14 to -15 years), and the distortion was larger in the more aggressive HER2+ and triple-negative tumors than in HR+ tumors. The genes associated with BTEC included known oncogenes (JAK1, TP73, PDGFRA, CCND1, STAT5B) and cancer-related pathways (Wnt, Hedgehog, ErbB).
What it means
The work indicates that DNA methylation in breast tumors does not follow a general pattern of accelerated aging and that epigenetic age must be measured with tissue-specific tools. Extreme epigenetic age deviations were associated with survival in HR+ patients in an exploratory analysis, pointing to a possible prognostic value that still needs validation.
Reference: Garma LD, Pernas S, Fullana B, Vethencourt A, Vicente Baz D, García Manrique T, et al. A breast tissue-specific epigenetic clock provides accurate chronological age predictions and reveals de-correlation of age and DNA methylation in tumor-adjacent and tumor samples. Epigenetics, 2026. DOI.
