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- Publisher Website: 10.1158/1078-0432.CCR-13-1217
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Article: Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer
Title | Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer |
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Authors | |
Issue Date | 2013 |
Publisher | American Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/ |
Citation | Clinical Cancer Research, 2013, v. 19 n. 20, p. 5788-97 How to Cite? |
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 = 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 = 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 = 6.62 x 10(-6), 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 = 2.29, P = 3.34 x 10(-5); overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012). |
Persistent Identifier | http://hdl.handle.net/10722/205915 |
ISSN | 2023 Impact Factor: 10.0 2023 SCImago Journal Rankings: 4.623 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Dai, W | en_US |
dc.contributor.author | Zeller, C | en_US |
dc.contributor.author | Masrour, N | en_US |
dc.contributor.author | Siddiqui, N | en_US |
dc.contributor.author | Paul, J | en_US |
dc.contributor.author | Brown, R | en_US |
dc.date.accessioned | 2014-10-20T09:45:00Z | - |
dc.date.available | 2014-10-20T09:45:00Z | - |
dc.date.issued | 2013 | en_US |
dc.identifier.citation | Clinical Cancer Research, 2013, v. 19 n. 20, p. 5788-97 | en_US |
dc.identifier.issn | 1078-0432 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/205915 | - |
dc.description.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 = 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 = 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 = 6.62 x 10(-6), 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 = 2.29, P = 3.34 x 10(-5); overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012). | en_US |
dc.language | eng | en_US |
dc.publisher | American Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/ | en_US |
dc.relation.ispartof | Clinical Cancer Research | en_US |
dc.subject.mesh | CpG Islands | en_US |
dc.subject.mesh | Cystadenocarcinoma, Serous - drug therapy - genetics - mortality - pathology | en_US |
dc.subject.mesh | DNA Methylation | en_US |
dc.subject.mesh | Ovarian Neoplasms - drug therapy - genetics - metabolism - mortality - pathology | en_US |
dc.subject.mesh | Promoter Regions, Genetic | en_US |
dc.title | Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer | en_US |
dc.type | Article | en_US |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-13-1217 | en_US |
dc.identifier.pmid | 23965899 | en_US |
dc.identifier.scopus | eid_2-s2.0-84886403668 | - |
dc.identifier.hkuros | 236721 | en_US |
dc.identifier.volume | 19 | en_US |
dc.identifier.issue | 20 | en_US |
dc.identifier.spage | 5788 | en_US |
dc.identifier.epage | 97 | en_US |
dc.identifier.isi | WOS:000325797600027 | - |
dc.publisher.place | United States | en_US |
dc.identifier.issnl | 1078-0432 | - |