title: Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies.
abstract: OBJECTIVE
  The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies.
  
  
  METHODS
  We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors.
  
  
  RESULTS
  The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51).
  
  
  CONCLUSIONS
  The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.
authors.affiliation: James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: apartin@jhmi.edu.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.affiliation: Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; MDxHealth, Inc., Irvine, California.
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Department of Urology, University of California-Los Angeles, Los Angeles, California.
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Marks
authors.affiliation: Lahey Hospital and Medical Center, Burlington, Massachusetts.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gee
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, East Virginia Medical School, Norfolk, Virginia.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.affiliation: Lahey Hospital and Medical Center, Burlington, Massachusetts.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Rieger-Christ
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Jones
authors.affiliation: Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.affiliation: James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Mangold
authors.affiliation: James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Trock
authors.affiliation: Leroy T. Canoles Jr. Cancer Research Center, East Virginia Medical School, Norfolk, Virginia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lance
authors.affiliation: MDxHealth, Inc., Irvine, California.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Bigley
authors.affiliation: MDxHealth, Inc., Irvine, California; Laboratory of Bioinformatics and Computational Genomics, Ghent University, Ghent, Belgium. Electronic address: wim.vancriekinge@mdxhealth.com.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.affiliation: James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
mesh_terms: D001706:Biopsy / Q000379:methods*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005500:Follow-Up Studies; D017491:Genes, APC; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D019564:Unnecessary Procedures / Q000706:statistics & numerical data
chemical_list: D004273:DNA, Neoplasm; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi
keywords: biopsy; epigenomics; methylation; prostate; prostatic neoplasms
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