title: Genome-scale screen for DNA methylation-based detection markers for ovarian cancer.
abstract: BACKGROUND
  The identification of sensitive biomarkers for the detection of ovarian cancer is of high clinical relevance for early detection and/or monitoring of disease recurrence. We developed a systematic multi-step biomarker discovery and verification strategy to identify candidate DNA methylation markers for the blood-based detection of ovarian cancer.
  
  
  RESULTS
  We used the Illumina Infinium platform to analyze the DNA methylation status of 27,578 CpG sites in 41 ovarian tumors. We employed a marker selection strategy that emphasized sensitivity by requiring consistency of methylation across tumors, while achieving specificity by excluding markers with methylation in control leukocyte or serum DNA. Our verification strategy involved testing the ability of identified markers to monitor disease burden in serially collected serum samples from ovarian cancer patients who had undergone surgical tumor resection compared to CA-125 levels. We identified one marker, IFFO1 promoter methylation (IFFO1-M), that is frequently methylated in ovarian tumors and that is rarely detected in the blood of normal controls. When tested in 127 serially collected sera from ovarian cancer patients, IFFO1-M showed post-resection kinetics significantly correlated with serum CA-125 measurements in six out of 16 patients.
  
  
  CONCLUSIONS
  We implemented an effective marker screening and verification strategy, leading to the identification of IFFO1-M as a blood-based candidate marker for sensitive detection of ovarian cancer. Serum levels of IFFO1-M displayed post-resection kinetics consistent with a reflection of disease burden. We anticipate that IFFO1-M and other candidate markers emerging from this marker development pipeline may provide disease detection capabilities that complement existing biomarkers.
authors.affiliation: Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Campan
authors.forename: Melissa
authors.initials: M
authors.lastname: Moffitt
authors.forename: Sahar
authors.initials: S
authors.lastname: Houshdaran
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Günter
authors.initials: G
authors.lastname: Daxenbichler
authors.forename: Tiffany
authors.initials: T
authors.lastname: Long
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Uma
authors.initials: U
authors.lastname: Chandavarkar
authors.forename: Lynda D
authors.initials: LD
authors.lastname: Roman
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001777:Blood Coagulation; D018394:CA-125 Antigen / Q000096:biosynthesis; D018899:CpG Islands; D004247:DNA / Q000097:blood; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008137:Longitudinal Studies; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D004247:DNA