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P15 Cervical intraepithelial neoplasia and cervical cancer: a genome wide association study (GWAS) of the UK biobank cohort
  1. S Bowden1,
  2. I Kalliala1,
  3. M Wielscher2,
  4. B Bodinier2,
  5. J Flanagan1,
  6. M Chadeau-Hyam2,
  7. M-R Jarvelin2 and
  8. M Kyrgiou1
  1. 1Surgery and Cancer
  2. 2Biostatistics and Epidemiology, Imperial College London, London, UK

Abstract

Introduction/Background Persistent infection with high-risk human papillomavirus (HPV) is causally associated with cervical cancer. However, only ∼1% of women with HPV infection progress to cervical neoplasia (CIN). It is estimated that heritability may explain 25–30% of total variation in liability for cervical cancer. Common genetic variants have been detected in HLA (Human Leukocyte Antigen) regions responsible for the immune response, but this is not well understood. We aimed to conduct the largest genome-wide association study (GWAS) of cervical cancer to date, using UK Biobank data to identify genetic polymorphisms associated with CIN and cervical cancer.

Methodology Using phenotypic data available from linked UK cancer registries, hospital ICD-10 records, operative procedures and participant interviews we identified 6378 women with CIN3/cervical cancer and 198,441 controls. With UK Biobank genotyping calls (Affymetrix UK Biobank Axiom® array) we conducted genome wide analyses, adjusting for population structure and potential confounders. As a stringent correction for multiple testing, we considered a pre-test significance level of 10-8 to declare single nucleotide polymorphisms (SNPs).

Results In the first UK Biobank iteration we have identified potential SNPs (p<5×10E-8) associated with CIN3/cervical cancer, with a large number of significant loci residing within Chromosomes 2 and 6 (figure1). Independent loci in the Major Histocompatibility Complex (MHC) region at 6p21.3 were associated with CIN3/cervical cancer, including loci adjacent to the MHC class 1 polypeptide-related sequence A gene (MICA) and HLA-DRB1 (figure 2), which replicates previously reported associations from published GWAS.

Conclusion We observed genetic variants significantly associated with CIN3/cervical cancer in both cohorts. Loci within the MHC may affect susceptibility to development of CIN3/cervical cancer through altered immune responses. We will next undertake fine-mapping within the UK Biobank cohort, to further classify any novel causal variants that may explain the estimated genetic susceptibility to cervical cancer.

Disclosure Funding provided by an NIHR Academic Clinical Fellowship (SL) and a Wellcome Trust Clinician Scientist Fellowship (SL). No conflicts of interest to declare.

Abstract P15 Figure 1

Manhattan plot of genome wide SNPs in Cervical Cancer/CIN3 in UK Biobank cohort

Abstract P15 Figure 2

HLA-DRB and HLA-DRQ locus zoom plots of SNPs associated with CIN3/Cervical cancer

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