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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.

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