Distinct epigenetic alterations and accelerated mitotic aging define second primary breast cancers

While the molecular features of FPBCs are well characterized, the biological underpinnings of SPBCs remain largely unexplored. SPBC tumors exhibited 11,321 differentially methylated CpG sites compared to FPBCs, with hypermethylation enriched at gene promoters involved in morphogenesis, hormone signaling, and cell adhesion.

Transcriptomic analysis revealed coordinated downregulation of hormone signaling pathways, including estradiol, progesterone, and androgen receptors, independent of somatic mutations. SPBC tumors also showed altered methylation at aging- and cancer-associated TF binding sites and significantly elevated mitotic age, indicative of epigenetic aging and increased proliferative history. SPBC tumors represent a distinct molecular subtype of breast cancer, defined by suppressed endocrine signaling and accelerated mitotic aging.