title: Global Hypomethylation (LINE-1) and Gene-Specific Hypermethylation (GSTP1) on Initial Negative Prostate Biopsy as Markers of Prostate Cancer on a Rebiopsy.
abstract: OBJECTIVE
  Men at risk of missed prostate cancer on a negative biopsy often undergo a rebiopsy. We evaluated whether global hypomethylation, measured through LINE-1 methylation, and GSTP1 hypermethylation on a negative biopsy are associated with subsequent prostate cancer diagnosis.
  
  
  METHODS
  We performed a case-control study nested in an unselected series of 737 men who received at least two prostate biopsies at least three months apart at the Molinette Hospital (Turin, Italy). Two pathology wards were included for replication purposes. The study included 67 cases and 62 controls in Ward 1 and 62 cases and 66 controls in Ward 2. We used pyrosequencing to analyze LINE-1 and GSTP1 methylation in the negative biopsies. Odds ratios (OR) of prostate cancer diagnosis were estimated using conditional logistic regression.
  
  
  RESULTS
  After mutual adjustment, GSTP1 hypermethylation was associated with an OR of prostate cancer diagnosis of 5.1 (95% confidence interval: 1.7-14.9) in Ward 1 and 2.0 (0.8-5.3) in Ward 2, whereas an association was suggested only for low LINE-1 methylation levels (<70% vs. 70%-74%) with an OR of 2.1 (0.5-9.1) in Ward 1 and 1.6 (0.4-6.1) in Ward 2. When the two wards were combined the association was stronger for tumors with Gleason score ≥ 4+3 [GSTP1 hypermethylation: 9.2 (2.0-43.1); LINE-1 (<70% vs. 70%-74%): 9.2 (1.4-59.3)]. GSTP-1 alone improved the predictive capability of the model (P = 0.007).
  
  
  CONCLUSIONS
  GSTP1 hypermethylation on a negative biopsy is associated with the risk of prostate cancer on a rebiopsy, especially of high-grade prostate cancer. Consistent results were found only for extremely low LINE-1 methylation levels.
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy. renatazelic@yahoo.com.
authors.forename: Renata
authors.initials: R
authors.lastname: Zelic
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fiano
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zugna
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Grasso
authors.affiliation: Division of Pathology, A.O. Città della Salute e della Scienza Hospital, Turin, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Delsedime
authors.affiliation: Division of Pathology, A.O. Città della Salute e della Scienza Hospital, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Daniele
authors.affiliation: Division of Pathology, A.O. Città della Salute e della Scienza Hospital, Turin, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Galliano
authors.affiliation: Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pettersson
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gillio-Tos
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Merletti
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Richiardi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D016022:Case-Control Studies; D019175:DNA Methylation; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D060787:Neoplasm Grading; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi