University of Oulu

Sarah J Bowden, Barbara Bodinier, Ilkka Kalliala, Verena Zuber, Dragana Vuckovic, Triada Doulgeraki, Matthew D Whitaker, Matthias Wielscher, Rufus Cartwright, Konstantinos K Tsilidis, Phillip Bennett, Marjo-Riitta Jarvelin, James M Flanagan, Marc Chadeau-Hyam, Maria Kyrgiou, Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study, The Lancet Oncology, Volume 22, Issue 4, 2021, Pages 548-557, ISSN 1470-2045,

Genetic variation in cervical preinvasive and invasive disease : a genome-wide association study

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Author: Bowden, Sarah J.1,2,3; Bodinier, Barbara4; Kalliala, Ilkka1,5;
Organizations: 1Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
2Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
3West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
4Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK
5Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
6Department of Urogynaecology, London North West Hospitals NHS Trust, London, UK
7Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
8Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
9Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland
10Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 13.3 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2021-05-10


Background: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls.

Methods: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40–69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer.

Findings: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84–0·91; p=1·07 × 10⁻⁹) and rs27069 (CLPTM1L; 0·88, 0·84–0·92; p=2·51 × 10⁻⁹), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21–1·32; p=2·51 × 10⁻²⁸), rs6938453 (MICA; 0·79, 0·75–0·83; p=1·97 × 10⁻¹⁷), rs55986091 (HLA-DQB1; 0·66, 0·60–0·72; p=6·42 × 10⁻²⁸), and rs9266183 (HLA-B; 0·73, 0·64–0·83; p=1·53 × 10⁻⁶). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10⁻⁷), and HLA-DQA1 (rs9272050; p=7·90 × 10⁻⁸). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64–3·69), older age at first pregnancy (0·80, 0·68–0·95), and number of sexual partners (1·95, 1·44–2·63) in the risk of developing cervical cancer.

Interpretation: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host–viral interactions.

Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.

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Series: The Lancet. Oncology
ISSN: 1470-2045
ISSN-E: 1474-5488
ISSN-L: 1470-2045
Volume: 22
Issue: 4
Pages: 548 - 557
DOI: 10.1016/S1470-2045(21)00028-0
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3122 Cancers
Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.
Copyright information: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.