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

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

Journal

The Lancet. Oncology
ISSN: 1474-5488
Titre abrégé: Lancet Oncol
Pays: England
ID NLM: 100957246

Informations de publication

Date de publication:
04 2021
Historique:
received: 16 10 2020
revised: 13 12 2020
accepted: 12 01 2021
entrez: 1 4 2021
pubmed: 2 4 2021
medline: 16 4 2021
Statut: ppublish

Résumé

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

Sections du résumé

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
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.

Identifiants

DOI: 10.1016/S1470-2045(21)00028-0 PMID: 33794208 PMC: PMC8008734
pubmed: 33794208
pii: S1470-2045(21)00028-0
doi: 10.1016/S1470-2045(21)00028-0
pmc: PMC8008734
pii:
doi:

Substances chimiques

CLPTM1L protein, human 0
HLA Antigens 0
Membrane Proteins 0
Neoplasm Proteins 0
PAX8 Transcription Factor 0
PAX8 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

548-557

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18281/A29019
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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Auteurs

Sarah J Bowden (SJ)

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

Barbara Bodinier (B)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Ilkka Kalliala (I)

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Verena Zuber (V)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Dragana Vuckovic (D)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Triada Doulgeraki (T)

West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

Matthew D Whitaker (MD)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Matthias Wielscher (M)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Rufus Cartwright (R)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK; Department of Urogynaecology, London North West Hospitals NHS Trust, London, UK.

Konstantinos K Tsilidis (KK)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Phillip Bennett (P)

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.

Marjo-Riitta Jarvelin (MR)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.

James M Flanagan (JM)

Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.

Marc Chadeau-Hyam (M)

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.

Maria Kyrgiou (M)

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. Electronic address: m.kyrgiou@imperial.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Isoantigènes › Antigènes d'histocompatibilité › Antigènes HLA › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription PAX › Facteur de transcription PAX-8 › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital féminin › Tumeurs de l'utérus › Tumeurs du col de l'utérus › Genetic variation in cervical preinvasive and...
questionsmedicales.fr › Maladies urogénitales › Maladies génitales › Maladies de l'appareil génital féminin › Maladies de l'utérus › Maladies du col utérin › Dysplasie du col utérin › Genetic variation in cervical preinvasive and...