{"doi":"10.1016/j.ebiom.2025.106065","title":"Neoantigenic properties of TP53 variants influence cancer risk in individuals with Li-Fraumeni syndrome","abstract":"BACKGROUND: Li-Fraumeni Syndrome (LFS) is a heterogenous cancer predisposition condition caused by pathogenic TP53 variants, characterised by a lifelong high risk of a broad spectrum of cancers. Certain pathogenic TP53 variants have been shown be immunogenic in a somatic context. Whether neoantigenicity contributes to LFS heterogeneity is unknown. In this study we analysed the correlations between predicted neoantigenic properties of pathogenic TP53 missense variants and LFS phenotypes. METHODS: MHC-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. A predicted neoantigenic score (PNS) was calculated for each variant. Association study was performed between PNS, LFS presentation and individual HLA-I genotyping, in individuals carrying TP53 germline pathogenic variants using data from mutation databases and clinical registries. Genotype-phenotype data were leveraged from the public TP53 database (germline dataset, n = 3446; 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. FINDINGS: Among individuals with frequent TP53 pathogenic variants, PNS was strongly correlated with median age at first cancer (range 18-43 years, R = 0.69, p = 0.0132). Compared to individuals with low PNS (<1) variants, those with high PNS (>2) variants showed delayed median age at first diagnosis (34 years vs. 25 years, p = 0.0009), fewer sarcomas (osteosarcoma [RR 0.29, p = 0.02]; soft-tissue [RR 0.41, p = 0.02]), and more cancer types typically not associated with LFS spectrum [RR 1.61, p = 0.02]. INTERPRETATION: MHC-I neoantigenic properties of TP53 variants are associated with differences in cancer risk and spectrum in individuals with pathogenic TP53 variants, suggesting that individual variant-specific immune response could contribute to the heterogenous presentation of LFS. FUNDING: European Commission, Fondation MSDAvenir, BMBF, Deutsche Kinderkrebsstiftung, European Regional Development Fund, Région Normandie, NIH, Mark Foundation, and Hertz Foundation.","journal":"EBioMedicine","year":2025,"id":535702,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":596194,"name":"Olivier Manches","orcid":"0000-0003-4509-2941","position":1,"is_corresponding":false},{"id":288786,"name":"Jonathan Gaucher","orcid":"0000-0002-1654-8009","position":2,"is_corresponding":false},{"id":1419849,"name":"Claire Freyçon","orcid":"0009-0006-1963-5171","position":3,"is_corresponding":false},{"id":1419850,"name":"D B Collantes Hoyos","orcid":"0000-0003-4868-8388","position":4,"is_corresponding":false},{"id":1172900,"name":"Sandrine Blanchet","orcid":"0000-0003-0779-6016","position":5,"is_corresponding":false},{"id":512902,"name":"Murielle Verboom","orcid":"0000-0001-8260-2045","position":6,"is_corresponding":false},{"id":1419851,"name":"Christina M. Dutzmann","orcid":"0009-0004-4549-6596","position":7,"is_corresponding":false},{"id":1419852,"name":"Sophie Coutant","orcid":"0000-0003-1255-8418","position":8,"is_corresponding":false},{"id":1420352,"name":"Jacqueline Bou","orcid":null,"position":9,"is_corresponding":false},{"id":962919,"name":"Bertrand Fin","orcid":null,"position":10,"is_corresponding":false},{"id":356095,"name":"Robert Olaso","orcid":"0000-0001-7631-9657","position":11,"is_corresponding":false},{"id":316773,"name":"Jean‐François Deleuze","orcid":"0000-0002-5358-4463","position":12,"is_corresponding":false},{"id":491782,"name":"Thierry Frébourg","orcid":"0000-0003-0399-4007","position":13,"is_corresponding":false},{"id":86527,"name":"Benjamin D. Greenbaum","orcid":"0000-0001-6153-8793","position":14,"is_corresponding":false},{"id":4075,"name":"Arnold J. Levine","orcid":"0000-0002-1871-6387","position":15,"is_corresponding":false},{"id":623655,"name":"Christian P. Kratz","orcid":"0000-0003-4120-5873","position":16,"is_corresponding":false},{"id":1061846,"name":"Gaëlle Bougeard","orcid":"0000-0002-1475-0254","position":17,"is_corresponding":false},{"id":54399,"name":"Pierre Hainaut","orcid":"0000-0002-1303-1610","position":18,"is_corresponding":false},{"id":1419848,"name":"Emilie Montellier","orcid":"0000-0001-5069-3536","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41370968","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}