title: Association of somatic DNA methylation variability with progression-free survival and toxicity in ovarian cancer patients.
abstract: BACKGROUND
  We have addressed whether inter-individual methylation variation in somatic (white blood cells, WBCs) DNA of ovarian cancer patients provides potential for prognostic and/or pharmacoepigenetic stratification.
  
  
  METHODS
  WBC DNA methylation was analysed by bisulphite pyrosequencing at ataxia telangiectasia mutated (ATM), estrogen receptor 1 (ESR1), progesterone receptor (PGR), mutL homologue 1 (MLH1), breast cancer susceptibility gene (BRCA1), secreted frizzled-related protein 1 (SFRP1), stratifin (SFN), retinoic acid receptor beta (RARB) loci and the repetitive element LINE1 in 880 SCOTROC1 trial patients [paclitaxel (Taxol)-carboplatin versus docetaxel (Taxotere)-carboplatin as primary chemotherapy for stage Ic-IV epithelial ovarian cancer].
  
  
  RESULTS
  We observed no significant associations (P < 0.005, after correction for multiple testing) for progression-free survival (PFS) using test and validation sets. However, we did identify mean SFN methylation associated with PFS (hazard ratio, HR = 1.01 per 1% increase in methylation, q = 0.028); particularly in the paclitaxel (HR = 1.01, q = 0.006), but not in the docetaxel arm in stratified analyses. Furthermore, higher methylation within the ESR1 gene was associated with CA125 response (odds ratio, OR = 1.06, q = 0.04) and with neuropathy (HR = 0.95, q = 0.002), but only in the paclitaxel arm of the trial.
  
  
  CONCLUSIONS
  This is the first study linking DNA methylation variability in WBC to clinical outcomes for any tumour type; the data generated on novel prognostic and pharmacoepigenetic DNA methylation biomarkers in the circulation now need independent further evaluation.
authors.affiliation: Epigenetics Unit, Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London.
authors.forename: J M
authors.initials: JM
authors.lastname: Flanagan
authors.forename: C S
authors.initials: CS
authors.lastname: Wilhelm-Benartzi
authors.forename: M
authors.initials: M
authors.lastname: Metcalf
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: R
authors.initials: R
authors.lastname: Brown
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002986:Clinical Trials as Topic; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007962:Leukocytes; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D017239:Paclitaxel
keywords: DNA methylation; clinical trial; ovarian cancer; pharmacoepigenetics; prognosis; toxicity