title: Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 × 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 × 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).
authors: Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK W12 0NN.
authors: Wei
authors: W
authors: Dai
authors: Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK W12 0NN.
authors: Constanze
authors: C
authors: Zeller
authors: Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK W12 0NN.
authors: Nahal
authors: N
authors: Masrour
authors: Department of Gynaecology, Glasgow Royal Infirmary, Glasgow, UK G31 2ER.
authors: Nadeem
authors: N
authors: Siddiqui
authors: Cancer Research UK Clinical Trials Unit, Glasgow University, The Beatson West of Scotland Cancer Centre, Level 0, 1053 Gt. Western Road, Glasgow, UK G12 0YN.
authors: James
authors: J
authors: Paul
authors: Epigenetics Unit, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK W12 0NN.|Section of Molecular Pathology, Institute for Cancer Research, Sutton UK SM2 5NG.
authors: Robert
authors: R
authors: Brown
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018899:CpG Islands; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D010984:Platinum
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