title: Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development.
abstract: BACKGROUND
  Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis.
  
  
  METHODS
  Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions.
  
  
  RESULTS
  H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort.
  
  
  CONCLUSIONS
  This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis.
  
  
  CONCLUSIONS
  Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies.
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide and Hanson Institute, Brisbane, Queensland, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Bianco-Miotto
authors.forename: Karen
authors.initials: K
authors.lastname: Chiam
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.forename: Shalini
authors.initials: S
authors.lastname: Jindal
authors.forename: Tanya K
authors.initials: TK
authors.lastname: Day
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thomas
authors.forename: Marie A
authors.initials: MA
authors.lastname: Pickering
authors.forename: Melissa A
authors.initials: MA
authors.lastname: O'Loughlin
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Ryan
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Raymond
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Horvath
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Stricker
authors.forename: Villis R
authors.initials: VR
authors.lastname: Marshall
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.forename: Judith A
authors.initials: JA
authors.lastname: Clements
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: David J
authors.initials: DJ
authors.lastname: Horsfall
authors.forename: Carmela
authors.initials: C
authors.lastname: Ricciardelli
mesh_terms: D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery
chemical_list: D006657:Histones; D017430:Prostate-Specific Antigen