Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers.

Rui Lan Huang, Fei Gu, Nameer B Kirma, Jianhua Ruan, Chun-liang Chen, Hui Chen Wang, Yu Ping Liao, Cheng Chang Chang, Mu Hsien Yu, Jay M. Pilrose, Ian M. Thompson, Hsuan Cheng Huang, Hui-ming Huang, Hung Cheng Lai, Kenneth P. Nephew

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25%. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating "hit" during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan-Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.

Original languageEnglish (US)
Pages (from-to)624-634
Number of pages11
JournalEpigenetics : official journal of the DNA Methylation Society
Volume8
Issue number6
StatePublished - Jun 2013
Externally publishedYes

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DNA Methylation
Ovarian Neoplasms
Biomarkers
Neoplasms
Methylation
Disease-Free Survival
Gene Silencing
Proportional Hazards Models
Epigenomics
Genes
Survival Rate
Technology
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers. / Huang, Rui Lan; Gu, Fei; Kirma, Nameer B; Ruan, Jianhua; Chen, Chun-liang; Wang, Hui Chen; Liao, Yu Ping; Chang, Cheng Chang; Yu, Mu Hsien; Pilrose, Jay M.; Thompson, Ian M.; Huang, Hsuan Cheng; Huang, Hui-ming; Lai, Hung Cheng; Nephew, Kenneth P.

In: Epigenetics : official journal of the DNA Methylation Society, Vol. 8, No. 6, 06.2013, p. 624-634.

Research output: Contribution to journalArticle

Huang, RL, Gu, F, Kirma, NB, Ruan, J, Chen, C, Wang, HC, Liao, YP, Chang, CC, Yu, MH, Pilrose, JM, Thompson, IM, Huang, HC, Huang, H, Lai, HC & Nephew, KP 2013, 'Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers.', Epigenetics : official journal of the DNA Methylation Society, vol. 8, no. 6, pp. 624-634.
Huang, Rui Lan ; Gu, Fei ; Kirma, Nameer B ; Ruan, Jianhua ; Chen, Chun-liang ; Wang, Hui Chen ; Liao, Yu Ping ; Chang, Cheng Chang ; Yu, Mu Hsien ; Pilrose, Jay M. ; Thompson, Ian M. ; Huang, Hsuan Cheng ; Huang, Hui-ming ; Lai, Hung Cheng ; Nephew, Kenneth P. / Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers. In: Epigenetics : official journal of the DNA Methylation Society. 2013 ; Vol. 8, No. 6. pp. 624-634.
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abstract = "Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25{\%}. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating {"}hit{"} during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan-Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.",
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AU - Gu, Fei

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AU - Ruan, Jianhua

AU - Chen, Chun-liang

AU - Wang, Hui Chen

AU - Liao, Yu Ping

AU - Chang, Cheng Chang

AU - Yu, Mu Hsien

AU - Pilrose, Jay M.

AU - Thompson, Ian M.

AU - Huang, Hsuan Cheng

AU - Huang, Hui-ming

AU - Lai, Hung Cheng

AU - Nephew, Kenneth P.

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N2 - Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25%. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating "hit" during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan-Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.

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