title: Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients.
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.
authors.affiliation: Graduate Institute of Life Sciences and.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Liao
authors.forename: Lin-Yu
authors.initials: LY
authors.lastname: Chen
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.forename: Po-Hsuan
authors.initials: PH
authors.lastname: Su
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chang
authors.forename: Mu-Hsien
authors.initials: MH
authors.lastname: Yu
authors.forename: Peng-Hui
authors.initials: PH
authors.lastname: Wang
authors.forename: Ming-Shyen
authors.initials: MS
authors.lastname: Yen
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006657:Histones / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality; D014411:Neoplastic Stem Cells; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D017422:Sequence Analysis, DNA; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000071183:Autophagy-Related Proteins; D014408:Biomarkers, Tumor; D006657:Histones; D034741:RNA, Small Interfering; C081018:histone H2B type 1-A; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases