Immune gene diversity and STING1 variants in shaping cancer immunity across different genetic ancestry populations

TL;DR

This study shows how genetic differences in immune genes, especially STING1, vary across populations and may affect cancer immunity and treatment.

Contribution

The study identifies STING1 variants as functional modulators of interferon signaling influenced by genetic ancestry.

Findings

Immune-related genes show higher variation than non-immune genes due to pathogen-driven selection.

STING1 variants rs11554776, rs78233829, and rs7380824 impact cGAS-STING1-IFN signaling in cancer cells.

Germline variations in immune genes may influence cancer immunity and should be considered in personalized medicine.

Abstract

As human populations migrated to diverse geographical regions, they encountered varying pathogens, leading to pronounced natural selection pressures on the immune system. Analysis of non-synonymous 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 the 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 (IFN) 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.

Hu et al. analyzed non-synonymous SNPs across diverse human populations and revealed divergent evolutionary pressures on immune- and cancer-related genes. By integrating population diversity with functional evaluation, they identified STING1 variants as modulators of interferon signaling. Their findings suggest that germline variations shaped by genetic ancestry may influence cancer immunity.

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