Molecular Portraits of Social Adversity in Breast Cancer: Neighborhood Disadvantage is Associated with Epigenetic Deregulation of Key Oncogenic Pathways.

Social adversity from neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa)-survival (BCSS). Although studies have identified associations between ND and DNA methylation (DNAme) or gene expression (mRNA), a study integrating DNAme and mRNA to understand how the epigenome regulates key biological pathways in ND, merits further inquiry. DNAme, mRNA, miRNA, and tRNA-derived fragment data were analyzed from 80 ER+/HER2- BCa samples. We analyzed the association between ND, DNAme, coding, and non-coding data to understand how the epigenome regulates biological pathways. 25 patients lived in ND and 55 in neighborhood advantage. In patients from ND, calcium signaling and cell adhesion pathways were hypermethylated, immune-related pathways hypomethylated, immune response genes upregulated, and estrogen response genes downregulated. Small RNA analysis showed differential expression of miRNA isoforms and tRNA-derived fragments related to ND. Subjective ND further correlated with epigenetic changes in calcium signaling, cell adhesion, and metabolic pathways, along with upregulation of proliferative and stemness pathways. We discovered novel associations between ND and epigenomic regulation of clinically relevant oncogenesis pathways associated with aggressive biology, such as estrogen response pathways. These findings lay the foundation for multi-institutional studies to validate our findings. This study demonstrates that ND, which is associated with shorter BCSS, is also associated with epigenetic reprogramming of key oncogenesis pathways. These findings highlight pathways through which ND may impact tumor biology and lay the foundation for cancer control policy and behavioral interventions that may reverse the negative effects of ND on cancer biology.