title: DNA methylation in human papillomavirus-infected cervical cells is elevated in high-grade squamous intraepithelial lesions and cancer.
abstract: OBJECTIVE
  DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population.
  
  
  METHODS
  A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves.
  
  
  RESULTS
  Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively).
  
  
  CONCLUSIONS
  DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies.
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Mi-Kyung
authors.identifier: http://orcid.org/0000-0001-6829-332X
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: In-Ho
authors.identifier: http://orcid.org/0000-0001-8856-3243
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Ki-Heon
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Yoo Kyung
authors.identifier: http://orcid.org/0000-0002-0621-8030
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Kyeong A
authors.initials: KA
authors.lastname: So
authors.affiliation: Department of Pathology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Sung Ran
authors.initials: SR
authors.lastname: Hong
authors.affiliation: Human Resource Biobank, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
authors.forename: Chang-Sun
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Division of AIDS, Center for Immunology and Pathology, National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongwon, Korea.
authors.forename: Mee-Kyung
authors.initials: MK
authors.lastname: Kee
authors.affiliation: Division of AIDS, Center for Immunology and Pathology, National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongwon, Korea.
authors.forename: Jee Eun
authors.initials: JE
authors.lastname: Rhee
authors.affiliation: Division of AIDS, Center for Immunology and Pathology, National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongwon, Korea.
authors.forename: Chun
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Hur
authors.affiliation: Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jong Sup
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea. kimonc111@naver.com.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Kim
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics; D065309:Atypical Squamous Cells of the Cervix / Q000473:pathology / Q000821:virology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics; D065006:Papanicolaou Test; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics; D012372:ROC Curve; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D014626:Vaginal Smears
chemical_list: C495401:ADCYAP1 protein, human; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D051761:Paired Box Transcription Factors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C070835:PAX1 transcription factor
keywords: Cervical Cancer Screening; Cervical Cytology; Cervical Intraepithelial Neoplasia; DNA Methylation; Uterine Cervical Neoplasms