{"doi":"10.1101/2021.08.12.456166","title":"Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility","abstract":"Abstract Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veterans Program cohort (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRS) did not predict autoimmune allele carrier status, suggesting these alleles provide new risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk unaccounted for by current PRS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221497,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":2185,"name":"David Laub","orcid":"0000-0001-5912-6458","position":1,"is_corresponding":false},{"id":23574,"name":"Meghana S. 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Hauger","orcid":"0000-0003-1509-1868","position":10,"is_corresponding":false},{"id":11352,"name":"Saiju Pyarajan","orcid":"0000-0002-9047-3762","position":11,"is_corresponding":false},{"id":11259,"name":"Philip S. Tsao","orcid":"0000-0001-7274-9318","position":12,"is_corresponding":false},{"id":368450,"name":"Gerald P. Morris","orcid":"0000-0002-1097-4453","position":13,"is_corresponding":false},{"id":98992,"name":"Rany M. Salem","orcid":"0000-0001-8816-6862","position":14,"is_corresponding":false},{"id":79256,"name":"Wesley K. Thompson","orcid":"0000-0002-1148-1976","position":15,"is_corresponding":false},{"id":310990,"name":"Kit Curtius","orcid":"0000-0002-2678-0960","position":16,"is_corresponding":false},{"id":262935,"name":"Maurizio Zanetti","orcid":"0000-0001-6346-8776","position":17,"is_corresponding":false},{"id":2188,"name":"Hannah Carter","orcid":"0000-0002-1729-2463","position":18,"is_corresponding":false},{"id":820059,"name":"James V. Talwar","orcid":"0000-0002-9520-1950","position":0,"is_corresponding":true}],"reference_count":192,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:55.215284Z","pmid":null,"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":[]}