Immune Gene Diversity and STING1 Variants in Shaping Cancer Immunity Across Different Genetic Ancestry Populations

As human populations migrated to diverse geographical regions, they encountered varying pathogens, leading to pronounced natural selection pressures on the immune system. Analysis of nonsynonymous single nucleotide polymorphisms (nsSNPs) across major geographically structured populations showed greater variation in immune-related genes than in non-immune genes, consistent with pathogen-driven selection, whereas cancer-related genes exhibited lower variation, reflecting evolutionary conservation of critical cellular functions. We prioritized nsSNPs in pattern recognition receptor genes based on population diversity and their association with type I interferon activity. Among the top-ranked variants were rs11554776, rs78233829, and rs7380824 in STING1, which demonstrated functional impacts on intrinsic cGAS-STING1-IFN signaling in cancer cells and potential influences on tumor immunity. We further conducted a genome-wide characterization of nsSNPs in immune-related genes across genetic ancestry populations and established a publicly accessible database. Our study suggests that genetic ancestry-related germline variations may influence cancer immunity and treatment, supporting their consideration in personalized medicine. Overall design: The SK-OV-3 parent cells and clones obtained from the dual CRISPR/Cas9 experiment were treated with 2'3'-cGAMP for 30 minutes and then allowed to rest for 4 hours. Subsequently, cells were harvested immediately and extracted using TRIzol Reagent. Illumina mRNA TruSeq library preparation was employed, followed by sequencing on an Illumina NovaSeq platform with paired-end 150 bp reads.