Association of genetic ancestry and molecular signatures with cancer survival disparities: a pan-cancer analysis

While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survivaldisparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which seven protein-coding genes (PAQR6, LIME1, SAP25, MXD3, CCER2, RFLNA, and CTSW) significantly interacted with GA and exacerbated observed survival disparities. These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.