title: Complex patterns of ETS gene alteration arise during cancer development in the human prostate.
abstract: An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.
authors.affiliation: Institute of Cancer Research, Male Urological Cancer Research Centre, Sutton, Surrey, UK. jeremy.clark@icr.ac.uk
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.forename: G
authors.initials: G
authors.lastname: Attard
authors.forename: S
authors.initials: S
authors.lastname: Jhavar
authors.forename: P
authors.initials: P
authors.lastname: Flohr
authors.forename: A
authors.initials: A
authors.lastname: Reid
authors.forename: J
authors.initials: J
authors.lastname: De-Bono
authors.forename: R
authors.initials: R
authors.lastname: Eeles
authors.forename: P
authors.initials: P
authors.lastname: Scardino
authors.forename: J
authors.initials: J
authors.lastname: Cuzick
authors.forename: G
authors.initials: G
authors.lastname: Fisher
authors.forename: M D
authors.initials: MD
authors.lastname: Parker
authors.forename: C S
authors.initials: CS
authors.lastname: Foster
authors.forename: D
authors.initials: D
authors.lastname: Berney
authors.forename: G
authors.initials: G
authors.lastname: Kovacs
authors.forename: C S
authors.initials: CS
authors.lastname: Cooper
mesh_terms: D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human