{"doi":"10.1002/ijc.33614","title":"Association of genomic variants at <scp><i>PAX8</i></scp> and <scp><i>PBX2</i></scp> with cervical cancer risk","abstract":"<jats:title>Abstract</jats:title><jats:p>Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta‐analysis, 2q14.1 (<jats:italic>PAX8</jats:italic>) and 6p21.32 (<jats:italic>PBX2</jats:italic>) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case‐control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at <jats:italic>PAX8</jats:italic> and rs2856437 at <jats:italic>PBX2</jats:italic>, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.91, <jats:italic>P</jats:italic> = 2.4 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.52, 95% CI 1.14‐2.02, <jats:italic>P</jats:italic> = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462<jats:italic>:</jats:italic> OR 0.80, 95% CI 0.68‐0.94, <jats:italic>P</jats:italic> = .006; rs2856437: OR 1.56, 95% CI 1.03‐2.36, <jats:italic>P</jats:italic> = .036) and with high‐grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70‐0.90, <jats:italic>P</jats:italic> = 1.9 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.58, 95% CI 1.15‐2.17, <jats:italic>P</jats:italic> = .005). A combined analysis of high‐grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73‐0.91, <jats:italic>P</jats:italic> = 2.4 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.57, 95% CI 1.18‐2.10, <jats:italic>P</jats:italic> = .002). No association was detected for rs2856437 with low‐grade dysplasia, while rs10175462 showed weak evidence of association (<jats:italic>P</jats:italic> = .05). RNA analyses in cervical samples revealed that <jats:italic>PAX8</jats:italic> transcripts were upregulated in HPV‐positive lesions (<jats:italic>P</jats:italic> = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA <jats:italic>PAX8‐AS1</jats:italic> (<jats:italic>P</jats:italic> &lt; .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (<jats:italic>PBX2</jats:italic>) with cervical disease and support <jats:italic>PAX8</jats:italic> as the first consistent non‐HLA cervical cancer susceptibility locus.</jats:p>","journal":"International Journal of Cancer","year":2021,"id":611187,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":748560,"name":"Yingying Wang","orcid":"0000-0001-6502-1388","position":1,"is_corresponding":false},{"id":1282606,"name":"Peter Schürmann","orcid":"0009-0004-6678-540X","position":2,"is_corresponding":false},{"id":1414191,"name":"Fabienne Hülse","orcid":null,"position":3,"is_corresponding":false},{"id":1572590,"name":"Qianqian Mao","orcid":null,"position":4,"is_corresponding":false},{"id":1566456,"name":"Matthias Jentschke","orcid":null,"position":5,"is_corresponding":false},{"id":1572591,"name":"Gerd Böhmer","orcid":null,"position":6,"is_corresponding":false},{"id":1572592,"name":"Hans‐Georg Strauß","orcid":null,"position":7,"is_corresponding":false},{"id":1572593,"name":"Christine Hirchenhain","orcid":null,"position":8,"is_corresponding":false},{"id":1572594,"name":"Monika Schmidmayr","orcid":null,"position":9,"is_corresponding":false},{"id":136913,"name":"Florian Müller","orcid":null,"position":10,"is_corresponding":false},{"id":1572595,"name":"Ingo Runnebaum","orcid":null,"position":11,"is_corresponding":false},{"id":305539,"name":"Alexander Hein","orcid":"0000-0003-2601-3398","position":12,"is_corresponding":false},{"id":1572596,"name":"Martin Koch","orcid":null,"position":13,"is_corresponding":false},{"id":715101,"name":"Matthias Ruebner","orcid":"0000-0002-2408-1138","position":14,"is_corresponding":false},{"id":55304,"name":"Matthias W. Beckmann","orcid":"0000-0002-8441-693X","position":15,"is_corresponding":false},{"id":33594,"name":"Peter A. Fasching","orcid":"0000-0003-4885-8471","position":16,"is_corresponding":false},{"id":1572597,"name":"Alexander Luyten","orcid":null,"position":17,"is_corresponding":false},{"id":305537,"name":"Matthias Dürst","orcid":"0000-0003-1235-1150","position":18,"is_corresponding":false},{"id":225530,"name":"Peter Hillemanns","orcid":"0000-0001-9829-3531","position":19,"is_corresponding":false},{"id":225515,"name":"Thilo Dörk","orcid":"0000-0002-9458-0282","position":20,"is_corresponding":false},{"id":1111913,"name":"Dhanya Ramachandran","orcid":"0000-0001-8139-7799","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Association of genomic variants at <scp><i>PAX8</i></scp> and <scp><i>PBX2</i></scp> with cervical cancer risk","abstract":"<jats:title>Abstract</jats:title><jats:p>Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta‐analysis, 2q14.1 (<jats:italic>PAX8</jats:italic>) and 6p21.32 (<jats:italic>PBX2</jats:italic>) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case‐control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at <jats:italic>PAX8</jats:italic> and rs2856437 at <jats:italic>PBX2</jats:italic>, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.91, <jats:italic>P</jats:italic> = 2.4 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.52, 95% CI 1.14‐2.02, <jats:italic>P</jats:italic> = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462<jats:italic>:</jats:italic> OR 0.80, 95% CI 0.68‐0.94, <jats:italic>P</jats:italic> = .006; rs2856437: OR 1.56, 95% CI 1.03‐2.36, <jats:italic>P</jats:italic> = .036) and with high‐grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70‐0.90, <jats:italic>P</jats:italic> = 1.9 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.58, 95% CI 1.15‐2.17, <jats:italic>P</jats:italic> = .005). A combined analysis of high‐grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73‐0.91, <jats:italic>P</jats:italic> = 2.4 × 10<jats:sup>−4</jats:sup>; rs2856437: OR 1.57, 95% CI 1.18‐2.10, <jats:italic>P</jats:italic> = .002). No association was detected for rs2856437 with low‐grade dysplasia, while rs10175462 showed weak evidence of association (<jats:italic>P</jats:italic> = .05). RNA analyses in cervical samples revealed that <jats:italic>PAX8</jats:italic> transcripts were upregulated in HPV‐positive lesions (<jats:italic>P</jats:italic> = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA <jats:italic>PAX8‐AS1</jats:italic> (<jats:italic>P</jats:italic> &lt; .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (<jats:italic>PBX2</jats:italic>) with cervical disease and support <jats:italic>PAX8</jats:italic> as the first consistent non‐HLA cervical cancer susceptibility locus.</jats:p>","is_dataset_classified":null,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"33905146","pmcid":null,"openalex_id":"https://openalex.org/W3157325377","authors":[],"funders":[{"funder_name":"Bruno and Helene Jöster Foundation","grant_id":"","title":null},{"funder_name":"Bruno and Helene Jöster Foundation","grant_id":"","title":null}],"total_grants":2,"fwci":2.2843,"citation_percentile":0.88667481,"influential_citations":0,"citation_trend":[{"year":2021,"count":4},{"year":2022,"count":4},{"year":2023,"count":2},{"year":2024,"count":6},{"year":2025,"count":1}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.33614","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.33614","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.33614","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ijc.33614","host_type":"publisher"},{"url":"https://doi.org/10.1002/ijc.33614","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/33905146","host_type":"repository"},{"url":"https://mediatum.ub.tum.de/1620574","host_type":"repository"},{"url":"https://mediatum.ub.tum.de/1625260","host_type":"repository"},{"url":"https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-166130","host_type":"repository"}],"fields_of_study":["Cervical Cancer and HPV Research","Cancer-related gene regulation","Cancer-related molecular mechanisms research"],"mesh_terms":[],"keywords":["Odds ratio","Cervical cancer","Medicine","Dysplasia","Confidence interval","Internal medicine","Gastroenterology","Oncology","Cervical intraepithelial neoplasia","Case-control study","Cancer","Gynecology","Single nucleotide polymorphism","Association study","Eqtl","Hpv Infection","Cervical Malignancy"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-01T16:29:51.152339Z","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":[]}