title: Integrated analysis reveals critical genomic regions in prostate tumor microenvironment associated with clinicopathologic phenotypes.
abstract: OBJECTIVE
  Recent studies suggest that tumor microenvironment (stroma) is important in carcinogenesis and progression. We sought to integrate global genomic structural and expressional alterations in prostate cancer epithelium and stroma and their association with clinicopathologic features.
  
  
  METHODS
  We conducted a genome-wide LOH/allelic imbalance (AI) scan of DNA from epithelium and stroma of 116 prostate cancers. LOH/AI hot or cold spots were defined as the markers with significantly higher or lower LOH/AI frequencies compared with the average frequency for markers along the same chromosome. These data were then integrated with publicly available transcriptome data sets and our experimentally derived data. Immunohistochemistry on an independent series was used for validation.
  
  
  RESULTS
  Overall, we identified 43 LOH/AI hot/cold spots, 17 in epithelium and stroma (P < 0.001), 18 only in epithelium (P < 0.001), and eight only in stroma (P < 0.001). Hierarchical clustering of expression data supervised by genes within LOH/AI hot/cold spots in both epithelium and stroma accurately separated samples into normal epithelium, primary cancer, and metastatic cancer groups, which could not be achieved with data from only epithelium. Importantly, our experimental expression data of the genes within the LOH/AI hot/cold spots in stroma accurately clustered normal stroma from cancer stroma. We also identified 15 LOH/AI markers that were associated with Gleason score, which were validated functionally in each compartment by transcriptome data. Independent immunohistochemical validation of STIM2 within a stromal significant LOH marker (identified as associated with Gleason grade) confirmed its downregulation in the transition from moderate to high Gleason grade.
  
  
  CONCLUSIONS
  Compartment-specific genomic and transcriptomic alterations accurately distinguish clinical and pathologic outcomes, suggesting new biomarkers for prognosis and targeted therapeutics.
authors.affiliation: Department of Quantitative Health Sciences, Lerner Research Institute, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ashida
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.forename: Gurkan
authors.initials: G
authors.lastname: Bebek
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D004273:DNA, Neoplasm / Q000737:chemistry*; D004847:Epithelial Cells / Q000737:chemistry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*; D054928:Validation Studies as Topic
chemical_list: D004273:DNA, Neoplasm