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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

TitlePromoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer
Authors
Issue Date2013
PublisherAmerican 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?
AbstractPURPOSE: 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 Identifierhttp://hdl.handle.net/10722/205915
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDai, Wen_US
dc.contributor.authorZeller, Cen_US
dc.contributor.authorMasrour, Nen_US
dc.contributor.authorSiddiqui, Nen_US
dc.contributor.authorPaul, Jen_US
dc.contributor.authorBrown, Ren_US
dc.date.accessioned2014-10-20T09:45:00Z-
dc.date.available2014-10-20T09:45:00Z-
dc.date.issued2013en_US
dc.identifier.citationClinical Cancer Research, 2013, v. 19 n. 20, p. 5788-97en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttp://hdl.handle.net/10722/205915-
dc.description.abstractPURPOSE: 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.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/en_US
dc.relation.ispartofClinical Cancer Researchen_US
dc.subject.meshCpG Islandsen_US
dc.subject.meshCystadenocarcinoma, Serous - drug therapy - genetics - mortality - pathologyen_US
dc.subject.meshDNA Methylationen_US
dc.subject.meshOvarian Neoplasms - drug therapy - genetics - metabolism - mortality - pathologyen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.titlePromoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian canceren_US
dc.typeArticleen_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-13-1217en_US
dc.identifier.pmid23965899en_US
dc.identifier.hkuros236721en_US
dc.identifier.volume19en_US
dc.identifier.issue20en_US
dc.identifier.spage5788en_US
dc.identifier.epage97en_US
dc.identifier.isiWOS:000325797600027-
dc.publisher.placeUnited Statesen_US

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