Epigenetic Markers of Cell Division and Ageing in Relation to Breast Cancer Survival

Breast cancer remains a major challenge to public health. Biomarkers may be useful to improve prediction of breast cancer survival. Several epigenetic markers of cell division and ageing based on DNA methylation have been proposed. In this study, we measured these epigenetic markers in breast tumours and assessed their prognostic value. We used genome-wide DNA methylation data measured in 1992 breast cancer tumours from the Melbourne Collaborative Cohort Study and publicly available datasets. We calculated four markers of cell division (epiTOC2, stemTOC, MiAge and CellDRIFT), two markers of chronological age (Horvath age and BTEC), and four markers of biological age (PhenoAge, GrimAge, MRscore and DunedinPACE). Cox regression models were used to assess the associations of age-adjusted epigenetic markers with 5-year overall survival, with adjustment for clinical variables. Effect modification by estrogen receptor (ER) status and molecular subtype was also investigated. After adjustment for age and stratification by study, higher levels of cell division markers were associated with poorer survival (e.g., epiTOC2: per one-standard-deviation increase, hazard ratio [HR] = 1.14, 95% CI: 1.03-1.27), whereas higher chronological age markers were linked to better prognosis (e.g., Horvath age: HR = 0.70, 95% CI: 0.61-0.82). Epigenetic markers of biological age showed variable associations. These associations were partly explained by the main clinicopathological variables at diagnosis and varied across subtypes. Our study revealed associations of several epigenetic markers with breast cancer survival. The associations were quite weak, suggesting these markers may have limited prognostic value. The varying associations observed among subtypes may reflect underlying biological differences that should be further investigated.