Integrated epigenomics analysis reveals a DNA methylation panel for endometrial cancer detection using cervical scrapings

Rui Lan Huang, Po Hsuan Su, Yu Ping Liao, Tzu I. Wu, Ya Ting Hsu, Wei Yu Lin, Hui Chen Wang, Yu Chun Weng, Yu Che Ou, Hui-ming Huang, Hung Cheng Lai

Research output: Contribution to journalArticle

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Abstract

Purpose: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. Experimental Design: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. Results: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%-96.0% and specificity of 78.7%-96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. Conclusions: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings.

Original languageEnglish (US)
Pages (from-to)263-272
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2017

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DNA Methylation
Endometrial Neoplasms
Epigenomics
Genes
Methylation
Tumor Biomarkers
Materials Testing
Myoma
Early Detection of Cancer
Research Design
Logistic Models
Odds Ratio
Databases
Confidence Intervals
Sensitivity and Specificity
Polymerase Chain Reaction
DNA
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Integrated epigenomics analysis reveals a DNA methylation panel for endometrial cancer detection using cervical scrapings. / Huang, Rui Lan; Su, Po Hsuan; Liao, Yu Ping; Wu, Tzu I.; Hsu, Ya Ting; Lin, Wei Yu; Wang, Hui Chen; Weng, Yu Chun; Ou, Yu Che; Huang, Hui-ming; Lai, Hung Cheng.

In: Clinical Cancer Research, Vol. 23, No. 1, 01.01.2017, p. 263-272.

Research output: Contribution to journalArticle

Huang, Rui Lan ; Su, Po Hsuan ; Liao, Yu Ping ; Wu, Tzu I. ; Hsu, Ya Ting ; Lin, Wei Yu ; Wang, Hui Chen ; Weng, Yu Chun ; Ou, Yu Che ; Huang, Hui-ming ; Lai, Hung Cheng. / Integrated epigenomics analysis reveals a DNA methylation panel for endometrial cancer detection using cervical scrapings. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 1. pp. 263-272.
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abstract = "Purpose: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. Experimental Design: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. Results: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7{\%}-96.0{\%} and specificity of 78.7{\%}-96.0{\%}. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8{\%}, specificity of 95.5{\%}, and odds ratio of 236.3 (95{\%} confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. Conclusions: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings.",
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T1 - Integrated epigenomics analysis reveals a DNA methylation panel for endometrial cancer detection using cervical scrapings

AU - Huang, Rui Lan

AU - Su, Po Hsuan

AU - Liao, Yu Ping

AU - Wu, Tzu I.

AU - Hsu, Ya Ting

AU - Lin, Wei Yu

AU - Wang, Hui Chen

AU - Weng, Yu Chun

AU - Ou, Yu Che

AU - Huang, Hui-ming

AU - Lai, Hung Cheng

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. Experimental Design: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. Results: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%-96.0% and specificity of 78.7%-96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. Conclusions: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings.

AB - Purpose: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. Experimental Design: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. Results: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%-96.0% and specificity of 78.7%-96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. Conclusions: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings.

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