title: Assessing the order of critical alterations in prostate cancer development and progression by IHC: further evidence that PTEN loss occurs subsequent to ERG gene fusion.
abstract: BACKGROUND
  ERG rearrangements and PTEN (phosphatase and tensin homolog deleted on chromosome 10) loss are two of the most common genetic alterations in prostate cancer. However, there is still significant controversy regarding the order of events of these two changes during the carcinogenic process. We used immunohistochemistry (IHC) to determine ERG and PTEN status, and calculated the fraction of cases with homogeneous/heterogeneous ERG and PTEN staining in a given tumor.
  
  
  METHODS
  Using a single standard tissue section from the index tumor from radical prostatectomies (N=77), enriched for relatively high grade and stage tumors, we examined ERG and PTEN status by IHC. We determined whether ERG or PTEN staining was homogeneous (all tumor cells staining positive) or heterogeneous (focal tumor cell staining) in a given tumor focus.
  
  
  RESULTS
  Fifty-seven percent (N=44/77) of tumor foci showed ERG positivity, with 93% of these (N=41/44) cases showing homogeneous ERG staining in which all tumor cells stained positively. Fifty-three percent (N=41/77) of tumor foci showed PTEN loss, and of these 66% (N=27/41) showed heterogeneous PTEN loss. In ERG homogeneously positive cases, any PTEN loss occurred in 56% (N=23/41) of cases, and of these 65% (N=15/23) showed heterogeneous loss. In ERG-negative tumors, 51.5% (N=17/33) showed PTEN loss, and of these 64.7% (N=11/17) showed heterogeneous PTEN loss. In a subset of cases, genomic deletions of PTEN were verified by fluorescence in situ hybridization in regions with PTEN protein loss as compared with regions with intact PTEN protein, which did not show PTEN genomic loss.
  
  
  CONCLUSIONS
  These results support the concept that PTEN loss tends to occur as a subclonal event within a given established prostatic carcinoma clone after ERG gene fusion. The combination of ERG and PTEN IHC staining can be used as a simple test to ascertain PTEN and ERG gene rearrangement status within a given prostate cancer in either a research or clinical setting.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gumuskaya
authors.forename: B
authors.initials: B
authors.lastname: Gurel
authors.forename: H
authors.initials: H
authors.lastname: Fedor
authors.forename: H-L
authors.initials: HL
authors.lastname: Tan
authors.forename: C A
authors.initials: CA
authors.lastname: Weier
authors.forename: J L
authors.initials: JL
authors.lastname: Hicks
authors.forename: M C
authors.initials: MC
authors.lastname: Haffner
authors.forename: T L
authors.initials: TL
authors.lastname: Lotan
authors.forename: A M
authors.initials: AM
authors.lastname: De Marzo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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