{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:42:22Z","timestamp":1792496542396,"version":"4.5.0"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004901","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Minas Gerais","doi-asserted-by":"publisher","award":["RED\u201000104\u201022"],"award-info":[{"award-number":["RED\u201000104\u201022"]}],"id":[{"id":"10.13039\/501100004901","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["313108\/2022\u20106"],"award-info":[{"award-number":["313108\/2022\u20106"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      This study aimed to evaluate the association between genetic variants and haplotypes of\n                      <jats:italic>ERAP1<\/jats:italic>\n                      and clinical outcomes in cervical cancer patients, utilizing data from the TCGA\u2010CESC and a cohort of Brazilian patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ERAP1<\/jats:italic>\n                      variants and haplotypes were evaluated in two distinct cohorts: whole\u2010exome sequencing (WES) data from 173 cervical cancer cases in the TCGA\u2010CESC dataset, and Sanger sequencing data from 52 Brazilian cervical cancer patients. The TCGA\u2010CESC data were employed for\n                      <jats:italic>in silico<\/jats:italic>\n                      analysis to identify significant\n                      <jats:italic>ERAP1<\/jats:italic>\n                      variants and haplotypes, which were subsequently evaluated\u00a0in Brazilian cervical cancer samples. The Tumor IMmune Estimation Resource (TIMER) tool was used to assess the association between\n                      <jats:italic>ERAP1<\/jats:italic>\n                      expression and immune cell infiltration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Haplotype analysis of\n                      <jats:italic>ERAP1<\/jats:italic>\n                      in the TCGA\u2010CESC dataset revealed that H005 (rs26653\u2014rs2287987\u2014rs30187\u2014rs10050860\u2014rs17482078\u2014rs27044) and H023 (rs26653\u2014rs27895\u2014rs30187\u2014rs27044) haplotypes were significantly associated with poorer survival outcomes. Homozygosity for H005 and the presence of H023 were strongly associated with both overall survival (OS) (HR\u2009=\u20099.591,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.00384; HR\u2009=\u200910.183,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.02862, respectively) and disease\u2010specific survival (DSS) (HR\u2009=\u200912.851,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.00162; HR\u2009=\u200915.183,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01191, respectively). TCGA\u2010CESC data showed that homozygosity for rs2287987 (p.Met349Val) was associated with an increased risk of death in both overall survival (OS) (HR\u2009=\u200911.043,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.00376) and disease\u2010specific survival (DSS) (HR\u2009=\u200913.833,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.00255), whereas rs30187 (p.Lys528Arg) demonstrated a protective effect for DSS, reducing mortality risk in both heterozygous (HR\u2009=\u20090.374,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04055) and homozygous (HR\u2009=\u20090.346,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03845) forms. However, although these variants were individually associated with survival outcomes in the dataset, this association was not retained in the multivariate analysis, suggesting that these variants may not have an independent prognostic effect. Similarly, no associations were found for these variants in the Brazilian cervical cancer cohort, suggesting that the impact of these variants on the prognosis of cervical cancer patients may be primarily influenced by the combination of variants. Furthermore,\n                      <jats:italic>ERAP1<\/jats:italic>\n                      expression levels were positively correlated with CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration (correlation coefficient\u2009=\u20090.264,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.00000960), which was associated with improved survival outcomes (HR\u2009=\u20090.006,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.049).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ERAP1<\/jats:italic>\n                      haplotype H005 homozygosity and the presence of H023 were linked to poorer prognosis, indicating their potential as prognostic biomarkers in cervical cancer patients. Individually, the rs2287987 variant showed a potential association with worse outcomes in the TCGA dataset; however, this finding was not replicated among Brazilian patients, suggesting the potential role of these variants when considered as haplotypes in the function of\n                      <jats:italic>ERAP1<\/jats:italic>\n                      . Additionally, the protective role of CD8+ T cell infiltration highlights its relevance as a possible therapeutic target for improving\u00a0survival in cervical cancer patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70170","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:00:17Z","timestamp":1792494017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic Impact of\n                    <i>ERAP1<\/i>\n                    Genetic Variants and Haplotypes in Cervical Cancer: Insights From\n                    <scp>TCGA<\/scp>\n                    \u2010\n                    <scp>CESC<\/scp>\n                    and a Brazilian Patient Cohort"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1447-5798","authenticated-orcid":false,"given":"Ana Luisa","family":"Dian","sequence":"first","affiliation":[{"name":"Grupo Inform\u00e1tica de Biossistemas, Bioengenharia e Gen\u00f4mica, Instituto Ren\u00e9 Rachou, Fiocruz Minas  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2594-0296","authenticated-orcid":false,"given":"Ana Paula Almeida","family":"Cunha","sequence":"additional","affiliation":[{"name":"Grupo Inform\u00e1tica de Biossistemas, Bioengenharia e Gen\u00f4mica, Instituto Ren\u00e9 Rachou, Fiocruz Minas  Belo Horizonte Brazil"},{"name":"Programa de P\u00f3s\u2010gradua\u00e7\u00e3o Stricto sensu em Biologia Computacional e Sistemas do Instituto Oswaldo Cruz, IOC, Fiocruz  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-5817","authenticated-orcid":false,"given":"Carolina Pereira de Souza","family":"Melo","sequence":"additional","affiliation":[{"name":"Grupo Inform\u00e1tica de Biossistemas, Bioengenharia e Gen\u00f4mica, Instituto Ren\u00e9 Rachou, Fiocruz Minas  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria do Desterro Soares Brand\u00e3o","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Department of Pathology Universidade Federal Do Maranh\u00e3o \u2010 UFMA  S\u00e3o Lu\u00eds Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Gabriela Reis","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Grupo Inform\u00e1tica de Biossistemas, Bioengenharia e Gen\u00f4mica, Instituto Ren\u00e9 Rachou, Fiocruz Minas  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9721","authenticated-orcid":false,"given":"Jeronimo Concei\u00e7\u00e3o","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Grupo Inform\u00e1tica de Biossistemas, Bioengenharia e Gen\u00f4mica, Instituto Ren\u00e9 Rachou, Fiocruz Minas  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"issue":"2","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve Years of SAMtools and BCFtools","volume":"10","author":"Danecek P.","year":"2021","journal-title":"GigaScience"},{"issue":"7","key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.3747\/pdi.2015.00261","article-title":"The 1000 Genomes Project: Welcome to a New World","volume":"35","author":"Devuyst O.","year":"2015","journal-title":"Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis"},{"issue":"1","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12859-017-1496-0","article-title":"PyHLA: Tests for the Association Between HLA Alleles and Diseases","volume":"18","author":"Fan Y.","year":"2017","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"e_1_2_13_5_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0029931","article-title":"A Functional Variant in ERAP1 Predisposes to Multiple Sclerosis","volume":"7","author":"Guerini F. 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