Divergent Molecular Networks Drive Ancestry-Related Colorectal Cancer Disparities

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality, with African-ancestry populations experiencing higher incidence and poorer outcomes. Although socioeconomic factors contribute, growing evidence suggests biological differences also play a role. However, ancestry-associated molecular features of CRC remain insufficiently defined, largely due to the underrepresentation of non-European populations in genomic studies. In this study, transcriptomic profiles of African-Black and European-White CRC patients from The Cancer Genome Atlas (TCGA) were compared to identify ancestry-associated molecular programs. Differential expression analysis identified dysregulated genes, and pathway enrichment revealed distinct biological processes. White patients exhibited coordinated immune–metabolic pathways, whereas Black patients showed fragmented modules centered on CRYBB2 and MAP9. Immune profiling using single-sample gene set enrichment analysis (ssGSEA) further demonstrated higher enrichment of interferon alpha response, allograft rejection, and complement activation in White patients, complemented by increased expression of immune checkpoint genes. Bootstrap resampling confirmed the robustness of these findings despite sample imbalance. These results provide novel evidence of ancestry-linked transcriptomic differences in CRC and underscore the importance of including diverse populations in cancer genomics to develop equitable biomarkers and therapeutic strategies.