Department of Quantitative Health Sciences, Lerner Research Institute, USA.
Clin Cancer Res. 2012 Mar 15;18(6):1578-87. doi: 10.1158/1078-0432.CCR-11-2535. Epub 2012 Jan 24.
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.
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.
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.
Compartment-specific genomic and transcriptomic alterations accurately distinguish clinical and pathologic outcomes, suggesting new biomarkers for prognosis and targeted therapeutics.
最近的研究表明肿瘤微环境（基质）在癌症发生和进展中起着重要作用。我们试图整合前列腺癌上皮和基质的全基因组结构和表达改变，并将其与临床病理特征联系起来。
我们对 116 例前列腺癌上皮和基质的 DNA 进行了全基因组 LOH/等位基因失衡（AI）扫描。LOH/AI 热点或冷点定义为与同一染色体上标记物的平均频率相比，LOH/AI 频率明显更高或更低的标记物。然后，将这些数据与公开的转录组数据集和我们的实验衍生数据进行整合。在独立的系列中进行免疫组织化学验证。
总的来说，我们鉴定了 43 个 LOH/AI 热点/冷点，17 个在上皮和基质中（P<0.001），18 个仅在上皮中（P<0.001），8 个仅在基质中（P<0.001）。在上皮和基质中的 LOH/AI 热点/冷点内的基因指导下对表达数据进行层次聚类，可以准确地将样本分为正常上皮、原发性癌症和转移性癌症组，而仅使用上皮数据则无法实现这一点。重要的是，我们对基质中 LOH/AI 热点/冷点内基因的实验表达数据准确地将正常基质与癌症基质聚类。我们还鉴定了 15 个与 Gleason 评分相关的 LOH/AI 标记物，这些标记物在每个隔室中都通过转录组数据进行了功能验证。在一个与 Gleason 分级相关的基质显著 LOH 标记物（STIM2）中进行独立的免疫组织化学验证，证实了其在从中度到高度 Gleason 分级的过渡中下调。
特定于隔室的基因组和转录组改变准确地区分了临床和病理结果，为预后和靶向治疗提供了新的生物标志物。
