Social genomics and cancer - untangling nature from nurture in squamous cell carcinoma outcomes

Outcomes in squamous cell carcinomas (SCCa) of the head and neck, esophagus, and lungs are increasingly linked to the complex interplay between social determinants of health (SDoH) and biological pathways. The emerging field of social genomics provides mechanistic insight into how the environmental and socioeconomic conditions may influence tumor biology through stress-mediated pathways, epigenetic modifications, and altered gene expression.

This review explores the role of adverse socioeconomic conditions such as neighborhood deprivation in shaping SCCa outcomes and the potential underlying mechanisms. In response to chronic stress, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system become activated, leading to dysregulated immune signaling and proinflammatory gene expression pattern collectively known as the Conserved Transcriptional Response to Adversity (CTRA). We discuss epigenetic modifications including DNA methylation (DNAm), histone modification, and micro RNA (miRNA) dysregulation as potential mediators of these stress-related effects. Studies show that SCCa may have distinct race- and neighborhood-specific DNAm patterns including differential methylation of PAX5, HOXA7, and TFPI genes, and altered expression of xenobiotic metabolism genes regulated by Nrf2, a major stress response transcription factor. Therapeutic strategies targeting these biological mediators including β-adrenergic blockers, DNA methyltransferase inhibitors (e.g., azacytidine, decitabine), histone deacetylase inhibitors (e.g., vorinostat), and BET inhibitors have shown variable efficacy in preclinical and clinical SCCa models. Incorporating social context into tumor genomic analysis through geospatial modeling and neighborhood epigenomic profiling may offer a novel opportunity for identifying population-level cancer risk patterns and therapeutic targets.

Social genomics provides a deeper understanding of the interaction of socio-environmental exposures with the epigenome and tumor biology influencing disparities in SCCa outcomes. Future research should integrate geospatial and multi-omics data to inform personalized cancer prevention and treatment strategies.