title: Methylation Levels of CADM1, MAL, and MIR124-2 in Cervical Scrapes for Triage of HIV-Infected, High-Risk HPV-Positive Women in Kenya.
abstract: OBJECTIVE
  To evaluate the value of cervical cell methylation markers in screening HIV-infected women also positive for high-risk human papillomavirus (hrHPV).
  
  
  METHODS
  Cross-sectional and prospective.
  
  
  METHODS
  Two hundred forty-eight HIV-infected hrHPV-positive women enrolled in a cervical cancer screening study in Nairobi, Kenya, had colposcopy-directed biopsy and histological diagnoses. Exfoliated cervical cells were used to measure methylation levels of the CADM1, MAL, and MIR124-2 genes using quantitative methylation-specific polymerase chain reaction. Methylation levels were summarized as cycle threshold (Ct) ratios compared with the β-actin gene. Median Ct ratios were compared across histological diagnoses, with 95% confidence intervals calculated by bootstrapping. Methylation levels at 6 months were assessed in 128 women who remained hrHPV positive.
  
  
  RESULTS
  All 3 methylation markers showed significantly (P < 0.001) raised median Ct ratios in women with cervical intraepithelial neoplasia (CIN) grade 3 compared with women with a normal cervix. When markers were combined into a single test, the area under the receiver operating characteristic curve for prediction of CIN2 or worse (CIN2+) was 0.80. When the test was calibrated to have similar specificity, sensitivity of the combined tri-marker test for CIN2+ was comparable with cytology [atypical squamous cells of undetermined significance or worse] (89% and 95%, respectively) and superior to visual inspection with acetic acid (85% vs 70%) and HPV16/18 genotyping (65% vs 40%). Among women with no CIN2+ at baseline and persistent hrHPV at 6-month follow-up, MAL-m1 and MIR124-2 Ct ratios increased significantly.
  
  
  CONCLUSIONS
  Methylation markers in combination with HPV testing may offer a full molecular screening strategy to the many HIV-infected women who are also hrHPV positive.
authors.affiliation: *International Agency for Research on Cancer, Lyon, France; †Kenya Medical Research Institute, Nairobi, Kenya; ‡Coptic Hospital, Coptic Hope Center, Nairobi, Kenya; §Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; and Departments of ‖Global Health; ¶Medicine; #Epidemiology, University of Washington, Seattle, WA.
authors.forename: Hugo
authors.initials: H
authors.lastname: De Vuyst
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschi
authors.forename: Martyn
authors.initials: M
authors.lastname: Plummer
authors.forename: Nelly R
authors.initials: NR
authors.lastname: Mugo
authors.forename: Samah R
authors.initials: SR
authors.lastname: Sakr
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tenet
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Albertus T
authors.initials: AT
authors.lastname: Hesselink
authors.forename: Michael H
authors.initials: MH
authors.lastname: Chung
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015415:Biomarkers; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000453:epidemiology / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D007630:Kenya / Q000453:epidemiology; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology / Q000378:metabolism*; D014218:Triage
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D004279:DNA, Viral; D007136:Immunoglobulins; C569026:MAL protein, human; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins