Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer

Author:

Ramachandran Dhanya12ORCID,Dennis Joe3,Fachal Laura3,Schürmann Peter12,Bousset Kristine12,Hülse Fabienne12,Mao Qianqian12,Wang Yingying12,Jentschke Matthias12,Böhmer Gerd4,Strauß Hans-Georg56,Hirchenhain Christine78,Schmidmayr Monika9,Müller Florian10,Runnebaum Ingo1112,Hein Alexander1314,Stübs Frederik1314,Koch Martin1314,Ruebner Matthias1314,Beckmann Matthias W1314,Fasching Peter A1314,Luyten Alexander151617,Dürst Matthias1314,Hillemanns Peter12,Easton Douglas F318,Dörk Thilo12ORCID

Affiliation:

1. Department of Gynaecology , Comprehensive Cancer Center, , Hannover 30625, Germany

2. Hannover Medical School , Comprehensive Cancer Center, , Hannover 30625, Germany

3. Centre for Cancer Genetic Epidemiology , Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

4. IZD Hannover , Hannover, Germany

5. Department of Gynaecology , University Clinics, , Halle-Wittenberg, Germany

6. Martin-Luther University , University Clinics, , Halle-Wittenberg, Germany

7. Department of Gynaecology , Clinics Carl Gustav Carus, , Dresden, Germany

8. University of Dresden , Clinics Carl Gustav Carus, , Dresden, Germany

9. Department of Gynaecology, Technische Universität München , Munich, Germany

10. Martin-Luther Hospital, Charite University , Berlin, Germany

11. Department of Gynaecology , Jena University Hospital, , Jena 07747, Germany

12. Friedrich-Schiller-University Jena , Jena University Hospital, , Jena 07747, Germany

13. Department of Gynaecology and Obstetrics , Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, , Erlangen 91054, Germany

14. Friedrich Alexander University of Erlangen–Nuremberg (FAU) , Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, , Erlangen 91054, Germany

15. Dysplasia Unit , Department of Gynaecology and Obstetrics, , Kronshagen, Germany

16. Mare Klinikum , Department of Gynaecology and Obstetrics, , Kronshagen, Germany

17. Department of Gynaecology, Wolfsburg Hospital , Wolfsburg, Germany

18. Centre for Cancer Genetic Epidemiology , Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK

Abstract

Abstract Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

Funder

Bruno and Helene Jöster Foundation

Hannover Biomedical Research School

Shanghai New Medical Union Hospital

Xuzhou Medical University

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

Reference45 articles.

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