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bioRxiv · 10.1101/2024.08.07.607038

Composite impact of genome-wide APOBEC mutations and HLA haplotype on cancer immunogenicity has a sex-biased survival impact

Larijani, M.·Borzooee, F.·Heravi-Moussavi, A.
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Abstract

APOBEC3A and APOBEC3B genome mutators drive tumor evolution and drug resistance but may also generate neoepitopes for cytotoxic T cells (CTL). Given the extensive polymorphism of Class I HLA, the CTL immunopeptidome, comprised of all 8-11mer peptides presented by an individuals six HLA class I alleles, varies person-to-person. We predicted the genome-wide impact of APOBEC3A/B-driven mutations on the immunogenicity of the immunopeptidomes of several thousand class I HLA alleles. Analysis of several billion APOBEC3-mediated mutations revealed that HLA class I alleles vary markedly in the susceptibility of their immunopeptidome to mutations. A subset of alleles of A1-A3 and B44 supertype supported increased neoepitopes. Notably, the immunogenicity changes supported by an individuals HLA class I alleles in response to APOBEC3 mutations predict survival in APOBEC3-mutated tumors and correlate with CTL activation. Thus, immunogenicity changes mediated by APOBEC3s impact survival, making HLA class I genotype a prognostic marker in APOBEC3-mutated tumors.

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Larijani, M., Borzooee, F., Heravi-Moussavi, A.. 2024-08-08. Composite impact of genome-wide APOBEC mutations and HLA haplotype on cancer immunogenicity has a sex-biased survival impact. https://doi.org/10.1101/2024.08.07.607038

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