title: Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies.
abstract: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Hypermethylation of genes such as glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) occurs with high frequency in prostate tumour tissue but is much less common in the benign prostate; however, the potential value of gene methylation biomarkers as an adjunct to biopsy histopathology has had little study. When measured in histologically benign prostate biopsy tissue, APC gene hypermethylation was found to have high negative predictive value and high sensitivity. GSTP1 hypermethylation was found to have lower performance than APC.
  
  
  OBJECTIVE
  To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.
  
  
  METHODS
  We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features. All men underwent repeat 12-core ultrasonography-guided biopsy. DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy. The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).
  
  
  RESULTS
  On repeat biopsy, 21/86 (24%) men had prostate cancer. APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06-1.36), indicating APC has significantly higher NPV. Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1. Combining both methylation markers produced a performance similar to that of APC alone. APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.
  
  
  CONCLUSIONS
  APC methylation provided a very high NPV with a low percentage of false-negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy. The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.
authors.affiliation: Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. btrock@jhmi.edu
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Trock
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Brotzman
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Mangold
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Bigley
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: David
authors.initials: D
authors.lastname: McLeod
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Jones
authors.forename: Songbai
authors.initials: S
authors.lastname: Wang
authors.forename: Theresa
authors.initials: T
authors.lastname: McAskill
authors.forename: Jyoti
authors.initials: J
authors.lastname: Mehrotra
authors.forename: Bhargavi
authors.initials: B
authors.lastname: Raghavan
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001707:Biopsy, Needle; D019175:DNA Methylation; D005188:False Negative Reactions; D017491:Genes, APC; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D051549:Glutathione S-Transferase pi
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