Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients

Yu Ping Liao, Lin Yu Chen, Rui-Lan Huang, Po Hsuan Su, Michael W Y Chan, Cheng Chang Chang, Mu Hsien Yu, Peng Hui Wang, Ming Shyen Yen, Kenneth P. Nephew, Hung Cheng Lai

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Abstract

DNA methylation contributes to tumor formation, development and metastasis. Epigenetic dysregulation of stem cells is thought to predispose to malignant development. The clinical significance of DNA methylation in ovarian tumor-initiating cells (OTICs) remains unexplored. We analyzed the methylomic profiles of OTICs (CP70sps) and their derived progeny using a human methylation array. qRT-PCR, quantitative methylation-specific PCR (qMSP) and pyrosequencing were used to verify gene expression and DNA methylation in cancer cell lines. The methylation status of genes was validated quantitatively in cancer tissues and correlated with clinicopathological factors. ATG4A and HIST1H2BN were hypomethylated in OTICs. Methylation analysis of ATG4A and HIST1H2BN by qMSP in 168 tissue samples from patients with ovarian cancer showed that HIST1H2BN methylation was a significant and independent predictor of progression-free survival (PFS) and overall survival (OS). Multivariate Cox regression analysis showed that patients with a low level of HIST1H2BN methylation had poor PFS (hazard ratio (HR), 4.5; 95% confidence interval (CI), 1.4-14.8) and OS (HR, 4.3; 95% CI, 1.3-14.0). Hypomethylation of both ATG4A and HIST1H2BN predicted a poor PFS (HR, 1.8; 95% CI, 1.0-3.6; median, 21 months) and OS (HR, 1.7; 95% CI, 1.0-3.0; median, 40 months). In an independent cohort of ovarian tumors, hypomethylation predicted early disease recurrence (HR, 1.7; 95% CI, 1.1-2.5) and death (HR, 1.4; 95% CI, 1.0-1.9). The demonstration that expression of ATG4A in cells increased their stem properties provided an indication of its biological function. Hypomethylation of ATG4A and HIST1H2BN in OTICs predicts a poor prognosis for ovarian cancer patients.

Original languageEnglish
Pages (from-to)1894-1906
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number7
DOIs
Publication statusPublished - Apr 1 2014
Externally publishedYes

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Neoplastic Stem Cells
Ovarian Neoplasms
Methylation
Confidence Intervals
DNA Methylation
Disease-Free Survival
Polymerase Chain Reaction
Survival
Neoplasms
Epigenomics
Stem Cells
Regression Analysis
Neoplasm Metastasis
Gene Expression
Recurrence
Cell Line
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients. / Liao, Yu Ping; Chen, Lin Yu; Huang, Rui-Lan; Su, Po Hsuan; Chan, Michael W Y; Chang, Cheng Chang; Yu, Mu Hsien; Wang, Peng Hui; Yen, Ming Shyen; Nephew, Kenneth P.; Lai, Hung Cheng.

In: Human Molecular Genetics, Vol. 23, No. 7, 01.04.2014, p. 1894-1906.

Research output: Contribution to journalArticle

Liao, YP, Chen, LY, Huang, R-L, Su, PH, Chan, MWY, Chang, CC, Yu, MH, Wang, PH, Yen, MS, Nephew, KP & Lai, HC 2014, 'Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients', Human Molecular Genetics, vol. 23, no. 7, pp. 1894-1906. https://doi.org/10.1093/hmg/ddt583
Liao, Yu Ping ; Chen, Lin Yu ; Huang, Rui-Lan ; Su, Po Hsuan ; Chan, Michael W Y ; Chang, Cheng Chang ; Yu, Mu Hsien ; Wang, Peng Hui ; Yen, Ming Shyen ; Nephew, Kenneth P. ; Lai, Hung Cheng. / Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 7. pp. 1894-1906.
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abstract = "DNA methylation contributes to tumor formation, development and metastasis. Epigenetic dysregulation of stem cells is thought to predispose to malignant development. The clinical significance of DNA methylation in ovarian tumor-initiating cells (OTICs) remains unexplored. We analyzed the methylomic profiles of OTICs (CP70sps) and their derived progeny using a human methylation array. qRT-PCR, quantitative methylation-specific PCR (qMSP) and pyrosequencing were used to verify gene expression and DNA methylation in cancer cell lines. The methylation status of genes was validated quantitatively in cancer tissues and correlated with clinicopathological factors. ATG4A and HIST1H2BN were hypomethylated in OTICs. Methylation analysis of ATG4A and HIST1H2BN by qMSP in 168 tissue samples from patients with ovarian cancer showed that HIST1H2BN methylation was a significant and independent predictor of progression-free survival (PFS) and overall survival (OS). Multivariate Cox regression analysis showed that patients with a low level of HIST1H2BN methylation had poor PFS (hazard ratio (HR), 4.5; 95{\%} confidence interval (CI), 1.4-14.8) and OS (HR, 4.3; 95{\%} CI, 1.3-14.0). Hypomethylation of both ATG4A and HIST1H2BN predicted a poor PFS (HR, 1.8; 95{\%} CI, 1.0-3.6; median, 21 months) and OS (HR, 1.7; 95{\%} CI, 1.0-3.0; median, 40 months). In an independent cohort of ovarian tumors, hypomethylation predicted early disease recurrence (HR, 1.7; 95{\%} CI, 1.1-2.5) and death (HR, 1.4; 95{\%} CI, 1.0-1.9). The demonstration that expression of ATG4A in cells increased their stem properties provided an indication of its biological function. Hypomethylation of ATG4A and HIST1H2BN in OTICs predicts a poor prognosis for ovarian cancer patients.",
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AU - Chan, Michael W Y

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