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

Autor: Ramachandran D; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Schürmann P; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Mao Q; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Wang Y; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Bretschneider LM; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Speith LM; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Hülse F; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Enßen J; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Bousset K; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Jentschke M; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Böhmer G; IZD Hannover, Hannover, Germany., Strauß HG; Department of Gynaecology, University Clinics, Martin-Luther University, Halle-Wittenberg, Germany., Hirchenhain C; Department of Gynaecology, Clinics Carl Gustav Carus, University of Dresden, Dresden, Germany., Schmidmayr M; Department of Gynaecology, Technische Universität München, Munich, Germany., Tarbiat J; Martin-Luther Hospital, Charite University, Berlin, Germany., Runnebaum I; Department of Gynecology, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany., Dürst M; Department of Gynecology, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany., Hein A; Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany., Koch M; Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany., Ruebner M; Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany., Ekici A; Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany., Beckmann MW; Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany., Fasching PA; Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany., Luyten A; Dysplasia Unit, Department of Gynecology and Obstetrics, Mare Klinikum, Kronshagen, Germany.; Department of Gynecology, Wolfsburg Hospital, Wolfsburg, Germany., Petry KU; Department of Gynecology, Wolfsburg Hospital, Wolfsburg, Germany., Hillemanns P; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany., Dörk T; Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2020 Nov 01; Vol. 147 (9), pp. 2458-2468. Date of Electronic Publication: 2020 Jul 10.
DOI: 10.1002/ijc.33171
Abstrakt: The human leukocyte antigen (HLA) 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 HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10 -6 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10 -5 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .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, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. 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 HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.
(© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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