Promoter CpG Island Methylation of Genes in Key Cancer Pathways Associates with Clinical Outcome in High-Grade Serous Ovarian Cancer

Abstract

Purpose: We aimed to identify DNA methylation biomarkers of progression-free survival (PFS) to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSOC) within biologically relevant ovarian cancer-associated pathways.Experimental Design: Association with PFS of CpG island (CGI) promoter DNA methylation at genes in the pathways Akt/mTOR, p53, redox, and homologous recombination DNA repair was sought with PFS as the primary objective in a prospectively collected ovarian cancer cohort (n ¼ 150). Significant loci were validated for associations between PFS, methylation, and gene expression in an independent The Cancer Genome Atlas (TCGA) data set of HGSOC (n ¼ 311).Results: DNA methylation at 29 CGI loci linked to 28 genes was significantly associated with PFS, independent from conventional clinical prognostic factors (adjusted P < 0.05). Of 17 out of the 28 genes represented in the TCGA data set, methylation of VEGFB, VEGFA, HDAC11, FANCA, E2F1, GPX4, PRDX2, RAD54L, and RECQL4 was prognostic in this independent patient cohort (one-sided P < 0.05, false discovery rate < 10%). A multivariate Cox model was constructed, with clinical parameters (age, stage, grade, and histologic type) and significant loci. The final model included NKD1, VEGFB, and PRDX2 as the three best predictors of PFS (P ¼ 6.62 Â 10 À6, permutation test P < 0.05). Focussing only on known VEGFs in the TCGA cohort showed that methylation at promoters of VEGFA, VEGFB, and VEGFC was significantly associated with PFS.Conclusions: A three loci model of DNA methylation could identify two distinct prognostic groups of patients with ovarian cancer (PFS: HR ¼ 2.29, P ¼ 3.34 Â 10 À5

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

“…Abundant studies based on molecular biology have shown that p16 gene promoter methylation can repress gene expression at the transcriptional level (Li et al, 1994;Gonzalez-Zulueta et al, 1995;Kondo et al, 2005). In addition, the promoter region of p16 in a methylated state might have impactions on inhibition of the gene expression and thereby promote the inactivation of p16 (Dai et al, 2013;Jeong et al, 2013). Elevated levels of p16 may usually lead to the formation of inhibitory CDK4/6-p16 complexes and a loss of stimulatory CDK4/6-cyclin D complexes (Semczuk and Jakowicki, 2004).…”

Epigenetic loss of heparan sulfate 3‐O‐sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

“…Abnormal DNA methylation may serve as a biomarker for early detection, outcome prediction, and individualized treatment . Hypermethylation of several genes, including those involved in DNA repair, AKT/mTOR, redox, apoptosis, cell adhesion and cancer stem cell signaling pathways, was reported to correlate with poor prognosis in ovarian cancer patients. Those epigenetics signatures revealed EOC heterogeneity and prognostic carcinogenesis that probably initiate by the diversity of genetic mutations .…”

“…Those epigenetics signatures revealed EOC heterogeneity and prognostic carcinogenesis that probably initiate by the diversity of genetic mutations . However, the prognostic value of only a few genes was validated using independent sets . The silencing of tumor suppressor genes that inhibit multiple oncogenic pathways is common in cancer, which may suggest a differential therapeutic response to targeted therapies .…”

“…4 However, the prognostic value of only a few genes was validated using independent sets. 19,20,22 The silencing of tumor suppressor genes that inhibit multiple oncogenic pathways is common in cancer, which may suggest a differential therapeutic response to targeted therapies. 24 Thus, DNA methylation may be a potential factor by which to stratify ovarian cancer patients who need further therapy.…”

Genome-wide DNA methylome analysis reveals novel epigenetically dysregulated non-coding RNAs in human breast cancer

“…Previous DNA methylation analyses have mainly focused on CpG islands (CGIs), which are highly clustered CpGs often located at gene promoter regions (Hatada et al 2006;Dai et al 2013). Mapping the DMRs to CGIs, we observed that most (31.85%) of the CGIs showed hyper-methylation in breast cancers (Figure 2A), associated with ~25.20% hyper-DMRs, which was significantly higher than random regions (p<0.001, Figure S2A, details in Text S1).…”