title: MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors.
abstract: Contemporary challenges of prostate cancer (PCa) include overdiagnosis and overtreatment, entailing the need for novel clinical tools to improve risk stratification and therapy selection. PCa diagnosis and prognostication might be perfected using epigenetic biomarkers, among which aberrant DNA methylation of microRNA promoters has not been systematically explored. Herein, we identified aberrantly methylated microRNAs promoters in PCa and assessed its diagnostic and prognostic biomarker potential.
  
  
  
  Using HumanMethylation450 BeadChip-based analysis differentially methylated CpGs in microRNA promoters were identified. Promoter methylation of six microRNAs (miR-34b/c, miR-129-2, miR-152, miR-193b, miR-663a and miR-1258) was analyzed by qMSP in three sets (180 prostatectomies, 95 urine sediments and 74 prostate biopsies). Biomarkers' diagnostic (validity estimates) and prognostic [disease-free (DFS) and disease-specific survival (DSS)] performance was assessed.
  
  
  
  Significantly higher promoter methylation levels in PCa were confirmed for six candidate microRNAs. Except for miR-152, all displayed AUC values higher than 0.90, with miR-1258 and miR-193b disclosing the best performance (AUC = 0.99 and AUC = 0.96, respectively). In urine samples, miR-193b showed the best performance (91.6% sensitivity, 95.7% specificity, AUC = 0.96). Moreover, higher miR-129-2 independently predicted for shorter DSS and miR-34b/c methylation levels independently predicted for shorter DFS and DSS.
  
  
  
  Quantitative miR-193b, miR-129-2 and miR-34b/c promoter methylation might be clinically useful PCa biomarkers for non-invasive detection/diagnosis and prognostication, both in tissue and urine samples.
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Research Center-LAB 3, F Bdg., 1st floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Torres-Ferreira
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Research Center-LAB 3, F Bdg., 1st floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.|Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.|Biomedical Sciences Graduate Program, Institute of Biomedical Sciences Abel Salazar- University of Porto (ICBAS-UP), Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Francisco Duarte
authors.initials: FD
authors.lastname: Menezes
authors.affiliation: Departments of Urology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Freitas
authors.affiliation: Departments of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Departments of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Antunes
authors.affiliation: Departments of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Bento
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Research Center-LAB 3, F Bdg., 1st floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.|Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto (ICBAS-UP), Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Research Center-LAB 3, F Bdg., 1st floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. carmenjeronimo@ipoporto.min-saude.pt.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto (ICBAS-UP), Porto, Portugal. carmenjeronimo@ipoporto.min-saude.pt.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000652:urine*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000145:classification* / Q000235:genetics / Q000652:urine; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C546783:MIRN192 microRNA, human; C546818:MIRN193 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs
keywords: Aberrant miR’s promoter methylation; Biomarkers; Detection; Prognosis; Prostate cancer