ABSTRACT: Neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa) survival. Although studies have identified that ND is associated with alterations in DNA methylation (DNAme) or gene expression, a comprehensive study integrating DNAme with coding (mRNA) and non-coding (miRNA, tRNA) transcriptomic data to understand how the epigenome regulates key biological pathways is lacking. DNAme, mRNA, miRNA, and tRNA-derived fragment data were analyzed from 80 ER+/HER2- BCa samples from Hispanic White women with no significant differences in genetic ancestry, BMI, smoking, alcohol, Oncotype DX scores, and stage. We analyzed the association between objective ND [Area Deprivation Index (ADI)], subjective ND [Neighborhood Social Environment Adversity Survey (NSEAS)], DNAme, coding, and non-coding data to understand how the epigenome regulates key biological pathways among women living in ND. The cohort was divided into neighborhood advantage (NA, ADI<5; n=55, 69%) and ND (ADI≥5; n=25, 31%). In tumors 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 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 key 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 and guide future treatment and cancer control interventions.
