Abstract
SummaryBackgroundMost 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.MethodsWe 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.FindingsWe 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.InterpretationOur 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.FundingNIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.
Highlights
Despite the introduction of screening and vaccination programmes, invasive cervical cancer remains one of the most common malignancies in women globally
The genome-wide association studies (GWASs) identified 3853 single-nucleotide polymorphisms (SNPs) and indels associated with the risk of invasive cervical cancer or CIN3
Functional analysis revealed that these associations targeted three genetic regions: the HLA region in which 3815 of the 3853 detected associations were located, PAX8 (2q14.1; lead SNP rs10175462 [odds ratio (OR) 0·87, 95% CI 0·84–0·91]; p=1·07 × 10–9), and CLPTM1L (5p15.33; lead SNP rs27069 [0·88, 0·84–0·92]; p=2·51 × 10–9; appendix pp 14 and 118)
Summary
Despite the introduction of screening and vaccination programmes, invasive cervical cancer remains one of the most common malignancies in women globally. Most infections are transient and cleared through an incompletely understood immune response, but a fraction of infected women develop a persistent HPV infection, which progresses to CIN or invasive cervical cancer.[3]. A number of factors, both host and viral, have been reported to affect HPV clearance and the risk of progression to cervical cancer. Host behavioural and environmental factors that might influence exposure to HPV or immune response to infection have been reported, including tobacco smoking,[5] hormonal contraceptives, and socioeconomic, reproductive, and sexual factors.[6] Family-based studies have reported family aggregation of cervical cancer, but were not able to discriminate between the effect of genes and shared environmental factors.[7,8] Population-based studies provide evidence for a genetic www.thelancet.com/oncology Vol 22 April 2021
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
