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

Ramachandran D, Schuermann P, Mao Q, Wang Y, Bretschneider LM, Speith LM, Huelse F, Enssen J, Bousset K, Jentschke M, Boehmer G, Strauss HG, Hirchenhain C, Schmidmayr M, Tarbiat J, Runnebaum I, Duerst M, Hein A, Koch M, Rübner M, Ekici AB, Beckmann M, Fasching P, Luyten A, Petry KU, Hillemanns P, Doerk T (2020)

Publication Type: Journal article

Publication year: 2020

Journal

DOI: 10.1002/ijc.33171

Abstract

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 atHLA-DQA1and rs2844511 atMICAandHCP5, 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 x 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 x 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 ofMICA,HCP5andHLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated withHLA-DQA1levels, specifically in HPV-positive samples, while rs2844511 was associated withMICAandHCP5levels. The risk allele of rs2844511 was required for correlations betweenMICAorHCP5withHLA-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 ofHLA-DQA1,HCP5andMICA, which may contribute to tumor immune evasion.

Authors with CRIS profile

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Institut für Zytologie und Dysplasie Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) Technische Universität Dresden Germany (DE) Technische Universität München (TUM) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Friedrich-Schiller-Universität Jena Germany (DE) Mare Klinikum Germany (DE) Klinikum Wolfsburg Germany (DE)

How to cite

APA:

Ramachandran, D., Schuermann, P., Mao, Q., Wang, Y., Bretschneider, L.-M., Speith, L.-M.,... Doerk, T. (2020). Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk,HPVstatus and gene expression levels. International Journal of Cancer. https://doi.org/10.1002/ijc.33171

MLA:

Ramachandran, Dhanya, et al. "Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk,HPVstatus and gene expression levels." International Journal of Cancer (2020).

BibTeX: Download