title: Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.
abstract: OBJECTIVE
  Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer.
  
  
  METHODS
  Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis.
  
  
  RESULTS
  We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases.
  
  
  CONCLUSIONS
  Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It could serve as a marker of the treatment response.
authors.affiliation: Servicio de Urología, Hospital Universitario de Getafe, Departamento Clínico, Facultad de Ciencias Biomédicas, Universidad Europea de Madrid, Laureate Universities, Getafe, Spain. Electronic address: javier.angulo@salud.madrid.org.
authors.forename: Javier C
authors.initials: JC
authors.lastname: Angulo
authors.affiliation: Servicio de Urología, Hospital Universitario de Getafe, Departamento Clínico, Facultad de Ciencias Biomédicas, Universidad Europea de Madrid, Laureate Universities, Getafe, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Andrés
authors.affiliation: Departamento de Biología de Sistemas, Unidad Docente de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Bilbao, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ashour
authors.affiliation: Servicio de Urología, Hospital Universitario Príncipe de Asturias, Universidad de Alcalá, Alcalá de Henares, Bilbao, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Chapado
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario de Cruces, Instituto BioCruces, Universidad del País Vasco, Bilbao, Spain.
authors.forename: Jose I
authors.initials: JI
authors.lastname: López
authors.affiliation: Departamento de Biología de Sistemas, Unidad Docente de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Bilbao, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ropero
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D019175:DNA Methylation; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000726:Androgen Antagonists
keywords: DNA methylation; androgens; castration; epigenomics; prostatic neoplasms