Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Medientyp: E-Artikel
Titel: Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels
Beteiligte: Ramachandran, Dhanya; Schürmann, Peter; Mao, Qianqian; Wang, Yingying; Bretschneider, Lisa‐Marie; Speith, Lisa‐Marie; Hülse, Fabienne; Enßen, Julia; Bousset, Kristine; Jentschke, Matthias; Böhmer, Gerd; Strauß, Hans‐Georg; Hirchenhain, Christine; Schmidmayr, Monika; Tarbiat, Johanna; Runnebaum, Ingo; Dürst, Matthias; Hein, Alexander; Koch, Martin; Ruebner, Matthias; Ekici, Arif; Beckmann, Matthias W.; Fasching, Peter A.; Luyten, Alexander; [...]
Erschienen: Wiley, 2020
Erschienen in: International Journal of Cancer
Sprache: Englisch
DOI: 10.1002/ijc.33171
ISSN: 0020-7136; 1097-0215
Schlagwörter: Cancer Research ; Oncology
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>The human leukocyte antigen (<jats:italic>HLA</jats:italic>) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single‐nucleotide polymorphisms in a large case‐control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at <jats:italic>HLA‐DQA1</jats:italic> and rs2844511 at <jats:italic>MICA</jats:italic> and <jats:italic>HCP5</jats:italic>, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79‐0.99, <jats:italic>P</jats:italic> = .036; rs2844511: OR 1.17, 95% CI 1.04‐1.31, <jats:italic>P</jats:italic> = .008) and with high‐grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70‐0.87, <jats:italic>P</jats:italic> = 7.1 × 10<jats:sup>−6</jats:sup>; rs2844511: OR 1.13, 95% CI 1.01‐1.26, <jats:italic>P</jats:italic> = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75‐0.91, <jats:italic>P</jats:italic> = 6.9 × 10<jats:sup>−5</jats:sup>; rs2844511: OR 1.14, 95% CI 1.04‐1.26, <jats:italic>P</jats:italic> = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low‐grade dysplasia (OR 1.26, 95% CI 1.04‐1.54, <jats:italic>P</jats:italic> = .019). In case‐only analyses, rs2844511 tended to predict HPV status (<jats:italic>P</jats:italic> = .044) and rs9272117 tended to associate with HPV16 (<jats:italic>P</jats:italic> = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of <jats:italic>MICA</jats:italic>, <jats:italic>HCP5</jats:italic> and <jats:italic>HLA‐DQA1</jats:italic>, suggesting extensive co‐regulation. All three genes were upregulated in HPV16‐positive samples. In stratified analyses, rs9272117 was associated with <jats:italic>HLA‐DQA1</jats:italic> levels, specifically in HPV‐positive samples, while rs2844511 was associated with <jats:italic>MICA</jats:italic> and <jats:italic>HCP5</jats:italic> levels. The risk allele of rs2844511 was required for correlations between <jats:italic>MICA</jats:italic> or <jats:italic>HCP5</jats:italic> with <jats:italic>HLA‐DQA1</jats:italic>. Altogether, our results support 6p21.32‐33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of <jats:italic>HLA‐DQA1</jats:italic>, <jats:italic>HCP5</jats:italic> and <jats:italic>MICA</jats:italic>, which may contribute to tumor immune evasion.</jats:p>
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