Neoantigenic properties of TP53 variants modify cancer risk in individuals with Li-Fraumeni syndrome

Abstract

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSLi-Fraumeni Syndrome (LFS) is an heterogenous cancer predisposition caused by pathogenic TP53 variants, characterized by a lifelong high risk of a broad spectrum of cancers. At least certain pathogenic TP53 variants have been shown be immunogenic in a somatic context. Whether neoantigenicity contributes to the heterogeneity of LFS is unknown. ObjectiveTo analyze the correlations between predicted neoantigenic properties of pathogenic TP53 missense variants and LFS patterns. DesignAssociation study between predicted MHC-I presentation scores for TP53 hotspot variants, LFS presentation and individual HLA-I genotyping in carriers of TP53 germline pathogenic variants using data from mutation databases and clinical registries. SettingMHC-I presentation scores were generated for the set of nonameric neo-peptides surrounding each TP53 missense variant against 145 different HLA-I using NetMHCpan 4.1 and the Allele Frequency Net Database. Genotype-phenotype data were leveraged from the public TP53 database (germline dataset, n=3,446; https://tp53.isb-cgc.org/) and two independent LFS clinical registries (n=339). Individual correlations between HLA-I genotyping, TP53 missense variants and phenotypes were investigated in a group of 173 subjects with LFS. ParticipantsIndividuals with LFS enrolled in LFS-registries in France and Germany were included. Main outcomes and measuresA predicted neoantigenic score (PNS) was calculated for each variant. Correlations with median age at first cancer, and cancer type were analyzed. ResultsAmong 709 carriers of frequent TP53 pathogenic variants, PNS was strongly correlated with median age at first cancer (range 18-43 years, p=0.01319, R=0.69). Compared to carriers of low PNS (2) variants showed delayed median age at first diagnosis (34 [CI95%, 29-40] vs. 25 years [CI95%, 22-27]), fewer sarcomas (osteosarcoma [RR 0.29, p-adj = 0.02]; soft-tissue [RR 0.41, p-adj = 0.02]), and more cancer types typically not associated with LFS [RR 1.61, p-adj = 0.02]. Conclusion and RelevanceMHC-I neoantigenic properties of TP53 variants modify cancer risk and spectrum in carriers of pathogenic TP53 variants, suggesting that individual variant-specific immune response may contribute to the heterogenous presentation of LFS.