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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)552-559
Number of pages8
JournalGynecologic Oncology
Volume135
Issue number3
DOIs
Publication statusPublished - Dec 1 2014

Fingerprint

Endometrial Hyperplasia
DNA Methylation
Methylation
Endometrial Neoplasms
Hyperplasia
Biomarkers
Carcinoma
Hysterectomy
Biopsy
Genes
Neoplasms
Polymerase Chain Reaction

Keywords

  • Atypical hyperplasia
  • Endometrial carcinoma
  • Endometrium
  • Epigenetics
  • Methylation

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Oncology
  • Medicine(all)

Cite this

DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia. / Lai, Hung Cheng; Wang, Yu Chi; Yu, Mu Hsien; Huang, Rui Lan; Yuan, Chiou-Chung; Chen, Kuan Ju; Wu, Chia Chun; Chiang, Kai Jo; Chao, Tai Kuang.

In: Gynecologic Oncology, Vol. 135, No. 3, 01.12.2014, p. 552-559.

Research output: Contribution to journalArticle

Lai, Hung Cheng ; Wang, Yu Chi ; Yu, Mu Hsien ; Huang, Rui Lan ; Yuan, Chiou-Chung ; Chen, Kuan Ju ; Wu, Chia Chun ; Chiang, Kai Jo ; Chao, Tai Kuang. / DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia. In: Gynecologic Oncology. 2014 ; Vol. 135, No. 3. pp. 552-559.
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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.",
keywords = "Atypical hyperplasia, Endometrial carcinoma, Endometrium, Epigenetics, Methylation",
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T1 - DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia

AU - Lai, Hung Cheng

AU - Wang, Yu Chi

AU - Yu, Mu Hsien

AU - Huang, Rui Lan

AU - Yuan, Chiou-Chung

AU - Chen, Kuan Ju

AU - Wu, Chia Chun

AU - Chiang, Kai Jo

AU - Chao, Tai Kuang

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Atypical hyperplasia

KW - Endometrial carcinoma

KW - Endometrium

KW - Epigenetics

KW - Methylation

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