title: DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia.
abstract: OBJECTIVE
  Women with atypical hyperplasia (AH) are often found to have endometrial carcinoma (EC) at hysterectomy. The purpose of this study was to evaluate whether the hypermethylation of specific genes found by methylomic approaches to the study of gynecologic cancers is a biomarker for EC in women with AH.
  
  
  METHODS
  We evaluated the methylation of AJAP1, HS3ST2, SOX1, and PTGDR from 61 AH patients undergoing hysterectomy. Endometrial biopsy samples were analyzed by bisulfite conversion and quantitative methylation-specific polymerase chain reaction. A methylation index was used to predict the presence of cancer. To confirm the silencing effects of DNA methylation, immunohistochemical analysis of AJAP1, HS3ST2, and SOX1 was performed using tissue microarray.
  
  
  RESULTS
  Fourteen (23%) patients had EC at hysterectomy. AJAP1, HS3ST2, and SOX1 were highly methylated in the EC patients' biopsy samples (p≤0.023). AJAP1, HS3ST2, and SOX1 protein expression was significantly higher in patients with AH only (p≤0.038). The predictive value of AJAP1, HS3ST2, and SOX1 methylation for EC was 0.81, 0.72, and 0.70, respectively. Combined testing of both AJAP1 and HS3ST2 methylation had a positive predictive value of 56%, methylation of any one of AJAP1, SOX1, or HS3ST2 had a 100% negative predictive value.
  
  
  CONCLUSIONS
  Hypermethylation of AJAP1, HS3ST2, and SOX1 is predictive of EC in AH patients. Testing for methylation of these genes in endometrial biopsy samples may be a hysterectomy-sparing diagnostic tool. Validation of these new genes as biomarkers for AH screening in a larger population-based study is warranted.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Obestetrics and Gynecology, Shuang Ho Hospital, Taipei University, Taipei, Taiwan; Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China; Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Mu-Hsien
authors.initials: MH
authors.lastname: Yu
authors.affiliation: Department of Obestetrics and Gynecology, Shuang Ho Hospital, Taipei University, Taipei, Taiwan.
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Obestetrics and Gynecology, Shuang Ho Hospital, Taipei University, Taipei, Taiwan.
authors.forename: Chiou-Chung
authors.initials: CC
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Kuan-Ju
authors.initials: KJ
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Nursing, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Kai-Jo
authors.initials: KJ
authors.lastname: Chiang
authors.affiliation: Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. Electronic address: chaotai.kuang@msa.hinet.net.
authors.forename: Tai-Kuang
authors.initials: TK
authors.lastname: Chao
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D019175:DNA Methylation; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D057890:Epigenomics; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D014408:Biomarkers, Tumor
keywords: Atypical hyperplasia; Endometrial carcinoma; Endometrium; Epigenetics; Methylation