title: Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study.
abstract: BACKGROUND
  Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylation as risk factors for HR-HPV persistence.
  
  
  METHODS
  Cervical cell samples from 955 women with HR-HPV infection and normal, borderline or mild dyskaryosis were retrieved from the archive of a population-based screening trial. Women were classified as cases or controls, reflecting the presence or absence [respectively] of any HR-HPV infection at a follow-up clinic at least 6 months from baseline. Cervical cell folate concentration and promoter methylation of five tumour suppressor genes were measured in independent samples from cases and controls.
  
  
  RESULTS
  A higher cervical cell folate concentration [P = 0.015] was an independent predictor of infection at follow-up, together with infection with HPV-16 or infection with multiple HR-HPV types. Methylation of the tumour suppressor gene DAPK was associated with a 2.64-fold [95% CI, 1.35-5.17] increased likelihood of HPV infection whilst CDH1 methylation was associated with a 0.53-fold [95% CI, 0.331-0.844] likelihood of HR-HPV infection at follow-up. When considering women with normal or abnormal cytology, the predictive effect of higher cervical cell folate was only seen in women with mild cytology [P = 0.021]; similarly the effect of DAPK methylation was seen in women with mild or borderline cytology [P < 0.05].
  
  
  CONCLUSIONS
  Higher cervical cell folate concentration and promoter methylation of the tumour suppressor gene, DAPK, in women with cervical cell dyskaryosis, are associated with increased risk of HR-HPV persistence.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Flatley
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sargent
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.forename: Jean M
authors.initials: JM
authors.lastname: Russell
authors.affiliation: Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2TN, UK. h.j.powers@sheffield.ac.uk.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Powers
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002584:Cervix Uteri / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D015995:Prevalence; D002583:Uterine Cervical Neoplasms / Q000209:etiology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000209:etiology
chemical_list: D005492:Folic Acid