Abstract C113: All by All browser analysis: Comparative assessment of colorectal cancer variant distributions in African and European ancestry populations in the All of Us research program

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Both incidence and mortality rates differ by ancestry, highlighting the importance of understanding the genetic contribution to colorectal cancer in diverse populations. This knowledge is vital for advancing precision medicine. Leveraging the All by All tables from the All of Us Research Program, we analyzed data from genome-wide association studies (GWAS) and rare variant association studies (RVAS) involving participants of African and European ancestries to examine genotype-phenotype relationships, comparing allele frequencies, effect sizes, functional annotations, and clinical relevance in CRC-associated genes. In participants of African ancestry, we identified suggestive associations in POT1, FGFR2, SLC9A9, RBFOX1, and CDH1. Notable correlations were found for rare variants in RBFOX1, DCC, DMD, and SLC9A9 in individuals of European descent, with gene burden analysis revealing enrichment in DCC and near-significant results for predicted loss-of-function variants in DMD. Individuals of African descent showed distinct associations in POT1, FGFR2, and NES. Cross-ancestry analyses identified RBFOX1, DCC, and SLC9A9 as common susceptibility loci, with a consistent missense burden observed in SLC9A9 across groups. RBFOX1 demonstrated allelic heterogeneity without a notable cumulative burden, whereas POT1 did not exhibit a gene burden. Pathogenic variant rates were slightly higher in individuals of European ancestry (2.63%) compared to those of African origin (2.57%), suggesting differences in genetic architecture across populations. Overall, this analysis reveals both shared and ancestry-specific rare variants that contribute to the development of colorectal cancer. It highlights the importance of acknowledging genetic disparities in genomic research and developing inclusive strategies for cancer risk assessment and intervention. Citation Format: Ijeoma J. Nnadozie, Barbara K. Fortini. All by All browser analysis: Comparative assessment of colorectal cancer variant distributions in African and European ancestry populations in the All of Us research program [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C113.