DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia

Hung-Cheng Lai; Yu-Chi Wang; Mu-Hsien Yu; Rui-Lan Huang; Chiou-Chung Yuan; Kuan-Ju Chen; Chia-Chun Wu; Kai-Jo Chiang; Tai-Kuang Chao

doi:10.1016/j.ygyno.2014.10.018

DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia

Gynecol Oncol. 2014 Dec;135(3):552-9. doi: 10.1016/j.ygyno.2014.10.018. Epub 2014 Oct 23.

Authors

Hung-Cheng Lai¹, Yu-Chi Wang², Mu-Hsien Yu², Rui-Lan Huang³, Chiou-Chung Yuan⁴, Kuan-Ju Chen⁵, Chia-Chun Wu⁶, Kai-Jo Chiang⁷, Tai-Kuang Chao⁸

Affiliations

¹ 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.
² Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
³ Department of Obestetrics and Gynecology, Shuang Ho Hospital, Taipei University, Taipei, Taiwan.
⁴ 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.
⁵ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
⁶ Department of Orthopaedic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
⁷ Department of Nursing, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
⁸ 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.

PMID: 25449566
DOI: 10.1016/j.ygyno.2014.10.018

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.

Keywords: Atypical hyperplasia; Endometrial carcinoma; Endometrium; Epigenetics; Methylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
DNA Methylation*
Endometrial Hyperplasia / genetics*
Endometrial Hyperplasia / pathology
Endometrial Neoplasms / genetics*
Endometrial Neoplasms / pathology
Epigenomics
Female
Humans
Male

Substances

Biomarkers, Tumor