Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes
Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes
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DOI：
10.1158/1078-0432.ccr-11-2535
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发表时间：
2012-03-15
影响因子：
11.5
通讯作者：
Eng, Charis
中科院分区：
文献类型：
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作者：
Ashida, Shingo;Orloff, Mohammed S.;Eng, Charis
目的：近年来的研究表明，肿瘤微环境（间质）在肿瘤的发生、发展中起着重要作用。我们试图整合全球基因组结构和表达的改变，在前列腺癌上皮和间质及其与临床病理features.Experimental Design：我们进行了全基因组洛缺失/等位基因不平衡（AI）扫描116前列腺癌上皮和间质的DNA。洛/AI热点或冷点定义为与同一染色体上沿着标记的平均频率相比，具有显著更高或更低的洛/AI频率的标记。然后将这些数据与公开可用的转录组数据集和我们的实验数据整合。结果：共发现43个洛/AI热点/冷点，其中17个位于上皮和间质（P < 0.001），18个仅位于上皮（P <0.001），8个仅位于间质（P < 0.001）。由上皮和间质中的洛/AI热/冷点内的基因监督的表达数据的分层聚类准确地将样品分成正常上皮、原发性癌症和转移性癌症组，这不能用仅来自上皮的数据实现。重要的是，我们在基质中的洛/AI热/冷点内的基因的实验表达数据准确地将正常基质与癌症基质聚类。我们还确定了15个与Gleason评分相关的洛/AI标记，通过转录组数据在每个区室中进行功能验证。STIM 2在基质显著洛缺失标记物（确定为与Gleason分级相关）内的独立免疫组化验证证实了其在从中度到高Gleason分级的过渡中的下调。结论：隔室特异性基因组和转录组学改变准确区分临床和病理结果，提示新的生物标志物用于预后和靶向治疗。临床癌症研究; 18（6）; 1578-87。（C）2012年AACR。
Purpose: 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.Experimental Design: 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. Clin Cancer Res; 18(6); 1578-87. (C)2012 AACR.