title: Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients' clinical outcome.
abstract: OBJECTIVE
  ERG-gene rearrangement defines a distinct molecular subtype of PCA with potential biological and clinical implications. To identify a molecular signature reflective of the downstream effects of ERG-mediated transcriptional regulation with prognostic implication in patients with prostate cancer (PCA).
  
  
  METHODS
  We used a singular value decomposition (SVD) bioinformatics approach to re-analyse gene expression data previously generated from 46 prostate tumours, and identified an ERG-like gene signature. The signature was validated on several patient cohorts and individual genes were correlated to ERG expression and PCA progression.
  
  
  RESULTS
  An ERG-like 10-gene signature was identified and validated in PCA cohorts of the physician health study (p115) (n = 110) in addition to three independent public datasets, and was significantly associated with disease progression, biochemical recurrence and PCA-specific mortality. Patients with the ERG-like signature were significantly associated with disease recurrence on univariate (hazard ratio [HR] 2.6; 95% confidence interval [CI]:1.3-5.2; P = 0.004) and multivariate analysis (HR 2.3; 95% CI:1.1-4.6, P = 0.016) compared with patients without this signature. Within the group of patients with Gleason score (GS) 6 and 7 PCA, the signature added prognostic value beyond GS and identified patients at higher risk of cancer deaths more accurately than GS alone or in combination with ERG status. Protein expression of the 10 genes were significantly associated with ERG and disease progression regardless of ERG status.
  
  
  CONCLUSIONS
  The characterized ERG-like signature was reflective of aggressive features of ERG-mediated transcription and was prognostically robust. The combination of this signature with clinicopathological variables should be validated prospectively to explore its clinical utility in stratifying patients with PCA and in identifying those at higher risk of metastatic and lethal disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada; Department of Oncology, University of Calgary, Calgary, AB, Canada; Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, AB, Canada.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.forename: Lars F
authors.initials: LF
authors.lastname: Petersen
authors.forename: Liang Hong
authors.initials: LH
authors.lastname: Teng
authors.forename: Travis
authors.initials: T
authors.lastname: Gerke
authors.forename: Ashraf
authors.initials: A
authors.lastname: Bakkar
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Mami
authors.forename: Shuhong
authors.initials: S
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Dolph
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: Reda
authors.initials: R
authors.lastname: Alhajj
mesh_terms: D019295:Computational Biology; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D060787:Neoplasm Grading; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
keywords: ERG rearrangements; ERG-like gene signature; Gleason score; molecular pathways; prognosis; prostate cancer