title: Aberrant DNA methylation of DLX4 and SIM1 is a predictive marker for disease progression of uterine cervical low-grade squamous intraepithelial lesion.
abstract: BACKGROUND
  A few uterine cervical low-grade squamous intraepithelial lesions (LSILs) are known to progress with high-risk human papillomavirus (hrHPV).
  
  
  METHODS
  One hundred and thirteen patients were classified into four groups according to their cervical cytology, hrHPV infection, and follow up. Cytology samples were examined for aberrant DNA methylation of DLX4 and SIM1 genes and protein expressions. CaSki cells were treated with 5-Aza-2'-deoxycytidine (5-aza-dC).
  
  
  RESULTS
  Group 1 was negative for intraepithelial lesions or malignancies. LSIL in group 2 showed a continuance of LSIL for longer than 365 days and LSIL in group 3 showed an upgrading to high-grade (H) SIL or higher (HSIL+) within 365 days of LSIL diagnosis. Group 4 was squamous cell carcinoma. All but group 1 were infected with hrHPV. Significant differences existed in the frequency of DNA methylation between groups 2 and 3 (p = 0.044), between groups 3 and 4 (p = 0.020) for DLX4, and between groups 1 and 3 (p = 0.0003), and groups 2 and 3 (p = 0.005) for the SIM1 gene. DLX4 protein expression was significantly reduced in the DLX4 methylation positive tissues (p = 0.008). The 5-aza-dC treatment restored DLX4 mRNA expressions of CaSki cells (p < 0.005). The LSIL cases with DNA methylation of the SIM1 gene, or both genes, progressed faster to HSIL+ than did the others (p = 0.033 and p = 0.045, respectively).
  
  
  CONCLUSIONS
  Aberrant DNA methylation of the DLX4 and SIM1 genes should be a novel progression marker for uterine cervical LSIL with hrHPV infection.
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan; Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Diagnostic Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakane
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Taniyama
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Akihisa
authors.initials: A
authors.lastname: Saito
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kuraoka
authors.forename: Toshinao
authors.initials: T
authors.lastname: Nishimura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C105304:DLX4 protein, human; C491094:SIM1 protein, human
keywords: DLX4; HPV; SIM1; aberrant DNA methylation; cervical cytology; epigenetics