: Publication 4953

Abstract

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.

14 Keywords

Adult
Aged
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA Antigens
Humans
Membrane Proteins
Middle Aged
Neoplasm Proteins
PAX8 Transcription Factor
Polymorphism, Single Nucleotide
Uterine Cervical Dysplasia
Uterine Cervical Neoplasms

16 Authors

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
FinnGen consortium

1 Application

Application ID	Title
21146	Genome-wide association study for cervical intraepithelial neoplasia and cervical cancer.

Title:	Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study
Journal:	The Lancet Oncology
Published:	1 Apr 2021
Pubmed:	https://pubmed.ncbi.nlm.nih.gov/33794208/
DOI:	https://doi.org/10.1016/s1470-2045(21)00028-0
URL:	http://www.thelancet.com/article/S1470204521000280/pdf