Genetic variation underlies ancestry-associated DNA methylation differences with immune regulatory potential in breast tumors

Population differences in breast cancer outcomes may reflect ancestry-linked genetic and molecular variation. Yet, how population-related genetic variation shapes tumor epigenetic and transcriptomic patterns remains unclear. Here, analyzing breast tumors of predominantly African and European genetic ancestry from The Cancer Genome Atlas, we identify 747 ancestry-associated differentially methylated sites. Methylation quantitative trait loci mapping shows that 60% of these sites are linked to at least one genetic variant, dominated by polymorphisms with differential frequencies across populations. Among differentially methylated sites that correlate with nearby gene expression, 61% are targeted by such variants, highlighting the interplay between genetic variation, DNA methylation, and gene expression. Immune response regulation, particularly involving HLA class II genes, is the most enriched for ancestry-related methylation effects, where mediation analysis supports a directional model of genetic variants influencing expression through DNA methylation. These findings reveal a strong genetic basis for ancestry-related epigenetic differences in breast tumors and their potential role in shaping the tumor-immune microenvironment. Genetic mapping of DNA methylation differences in breast tumours of predominantly African and European ancestry patients identifies population-related genetic variation effects with downstream regulatory potential, strongly linked to genes involved in immune regulation.