title: Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer.
abstract: New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5' (labelled green) and 3' (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.
authors.affiliation: Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK.
authors.forename: G
authors.initials: G
authors.lastname: Attard
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.forename: L
authors.initials: L
authors.lastname: Ambroisine
authors.forename: G
authors.initials: G
authors.lastname: Fisher
authors.forename: G
authors.initials: G
authors.lastname: Kovacs
authors.forename: P
authors.initials: P
authors.lastname: Flohr
authors.forename: D
authors.initials: D
authors.lastname: Berney
authors.forename: C S
authors.initials: CS
authors.lastname: Foster
authors.forename: A
authors.initials: A
authors.lastname: Fletcher
authors.forename: W L
authors.initials: WL
authors.lastname: Gerald
authors.forename: H
authors.initials: H
authors.lastname: Moller
authors.forename: V
authors.initials: V
authors.lastname: Reuter
authors.forename: J S
authors.initials: JS
authors.lastname: De Bono
authors.forename: P
authors.initials: P
authors.lastname: Scardino
authors.forename: J
authors.initials: J
authors.lastname: Cuzick
authors.forename: C S
authors.initials: CS
authors.lastname: Cooper
mesh_terms: D000368:Aged; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000401:mortality*; D012697:Serine Endopeptidases / Q000235:genetics*; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human