Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor-Microenvironment Associated with Clinico-pathologic Phenotypes
Menée sur 116 échantillons de tissus (épithélium et stroma) prélevés sur des patients atteints d'un cancer de la prostate, cette étude identifie des anomalies génomiques, spécifiques de l'un ou l'autre compartiment du micro-environnement tumoral, en association avec des caractéristiques pathologiques et cliniques
Purpose: Recent studies suggest 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 clinico-pathologic features. Experimental Design: We performed a genome-wide loss-of-heterozygosity/allelic-imbalance (LOH/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 datasets and our experimentally-derived data. Immunohistochemistry on an independent series was utilized for validation. Results: We identified 43 LOH/AI hot-/cold-spots, 17 in epithelium and stroma (p<0.001), 18 only in epithelium (p<0.001), and 8 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. Immunohistochemical validation of STIM2 within a stromal significant LOH marker (identified as associated with Gleason grade) confirmed its down-regulation in the transition from moderate to high Gleason grade. Conclusions: Compartment-specific genomic and transcriptomic alterations accurately distinguish clinical and pathological outcomes, suggesting new biomarkers for prognosis and targeted therapeutics.
Clinical Cancer Research , résumé, 2012