Affiliation:
1. Department of Gynaecology, Comprehensive Cancer Center Hannover Medical School Hannover Germany
2. IZD Hannover Hannover Germany
3. Department of Gynaecology, University Clinics Martin‐Luther University Halle‐Wittenberg Germany
4. Department of Gynaecology, Clinics Carl Gustav Carus University of Dresden Dresden Germany
5. Department of Gynaecology Technische Universität München Munich Germany
6. Martin‐Luther Hospital Charite University Berlin Germany
7. Department of Gynaecology and Obstetrics Klinikum Esslingen Esslingen am Neckar Germany
8. Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen‐EMN, Friedrich Alexander University of Erlangen–Nuremberg (FAU) Erlangen Germany
9. Institute of Human Genetics Friedrich‐Alexander University of Erlangen‐Nürnberg Erlangen Germany
10. Dysplasia Unit, Department of Gynecology and Obstetrics Mare Klinikum Kronshagen Germany
11. Department of Gynaecology Wolfsburg Hospital Wolfsburg Germany
12. Department of Gynaecology, Jena University Hospital Friedrich‐Schiller‐University Jena Jena Germany
Abstract
Cervical cancer is the fourth most common cancer in females. Genome‐wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital‐based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55–0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17–2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest eQTL pairs were rs9272117 and HLA‐DRB6 (p = 1.9x10E‐5), rs1056429 and HLA‐DRB5 (p = 2.5x10E‐4), and rs535777 and HLA‐DRB1 (p = 2.7x10E‐4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA‐B, LTB, NFKBIL1) or downregulated (HLA‐C, HLA‐DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ‐IFN led to a dose‐dependent induction of HCP5, HLA‐B, HLA‐C, HLA‐DQB1, HLA‐DRB1, HLA‐DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation‐responsive in cervical epithelium and associate with HPV (HCP5, HLA‐B, HLA‐C) and/or with genomic cervical cancer risk variants (HLA‐DRB1, HLA‐DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV‐infection.