DNA methylation age deceleration is correlated with a poor survival in triple-negative breast cancer

Epigenetic age acceleration/deceleration (EAA/EAD), measured using DNA methylation, is an emerging biomarker of biological aging and has been linked to adverse outcomes in various cancers. However, its prognostic role across diverse molecular subtypes of breast cancer (BC), particularly in the aggressive triple-negative breast cancer (TNBC) subtype, requires further investigation. This study aimed to investigate the association between EAA/EAD and clinical outcomes in BC. In total, 1,674 BC samples with Illumina 450 k or EPIC array data were collected for epigenetic age (epiAge) and EAA/EAD estimation. EpiAge and EAA/EAD were computed utilizing four different clocks (Horvath2013, PhenoAge, ZhangQ2019, and EpiTOC) and compared among different BC subtypes: Luminal A/B, HER2 + , Normal-like, and TNBC. Cox regression analysis and the log-rank test were employed to assess the association of EAA/EAD with BC survival. Epigenetic age alterations were observed across all BC subtypes; notably, EAD was most pronounced in the TNBC subtype. Multivariate analysis revealed that EAD (indicating a younger epiAge than chronological age) was significantly associated with a higher hazard ratio (HR = 2.03, 95% CI: 1.06–3.90, p = 0.03) and worse survival (log-rank test, p = 0.029) in the TNBC subtype. EAD was significantly associated with poor survival in TNBC and may represent a potential prognostic marker, although further validation is required. This observation raises the possibility that biological aging, as reflected in DNA methylation patterns, may play a role in the aggressiveness of TNBC and could serve as a biomarker for risk stratification.