Abstract
OBJECTIVE: This study investigates the association between HLA-A and -B allele diversity, Fusobacterium nucleatum Fap2 protein-derived antigenic coverage, and colorectal cancer (CRC) epidemiology across diverse populations. METHODS: We examined 75 HLA-I alleles and explored 698 potential HLA-A and B-restricted Fap2-derived antigens, assessing how 21 countries may respond to these peptides based on their HLA-I distribution frequencies. Additionally, we correlated in-silico predicted Fap2 population coverage with CRC epidemiology. CRC incidence and mortality data were obtained from the Global Cancer Observatory, and HLA-A and HLA-B allele frequencies from the Allele Frequency Net Database. Binding predictions for Fap2 antigens were performed using netMHCpan4, with stringent selection criteria applied to identify relevant peptides. Population coverage was calculated using the IEDB population coverage tool, and data analysis conducted using the R programming language. RESULTS: Clustering of HLA-A and -B allele frequencies partially differentiated countries with lower CRC incidence from others. Distinct patterns of Fap2 protein coverage were observed among different populations. interestingly, we found a significant inverse correlation between CRC incidence (p = 0.0037, R = -0.6) and predicted Fap2 antigen coverage, as well as CRC mortality (p = 0.013, R = -0.53). Furthermore, we identified a specific set of Fap2-derived peptides that bind to HLA supertypes, providing a global coverage of 99.04%. CONCLUSION: Our population-based study is the first to demonstrate that higher Fap2 coverage is associated with lower CRC incidence, underscoring the potential significance of Fap2-specific CD8+ T cell responses in CRC tumorigenesis.