The Prostate Cancer Tumor Microenvironment Exhibits Differentially Expressed Gene

描述（由申请人提供）：我们已经开发了用于确定构成前列腺癌（包括基质细胞）的四种主要细胞类型的细胞特异性基因表达的方法。这些研究揭示了数百种显着差异表达将正常基质与肿瘤邻近基质区分开来。这些差异已被用来开发基于几乎仅在基质中表达的基因的诊断分类器。诊断分类器在 300 多个独立的前列腺癌测试集中准确识别肿瘤的存在或不存在，其中包括包含基于一个的微阵列数据的子集。此外，分类器基因的子集准确地识别与表明预后潜力的不良结果相关的“反应性”基质与正常基质。我们假设这种基于基质的分类器可应用于重复活检的患者 1 的阴性临床活检以确定肿瘤的存在，从而在重复活检结果之前 6 - 12 个月提供早期检测。由于每年一百万个活检中大部分呈阴性，并且约 190,000 个计划进行重复活检，因此这是一个巨大的未满足的需求，没有公认的生物标志物用于诊断和/或早期检测阴性活检病例。在目标 1 和 2 中，建议使用独立测试阵列数据进行验证，并使用 LCM 制备的样品进行验证。目标 3 是一项针对新患者的前瞻性临床研究，经 UCI SPECS 联盟和西北大学 SPORE 同意，收集患者的阴性活检样本以进行重复活检。重复活检结果用于检验以下假设：72 个预测探针组是有效的诊断、早期检测和预后生物标志物。由于对每个同意患者的分析是在重复活检时完成的，因此早期检测的临床前瞻性研究是可能的。这是阴性活检材料的新颖且罕见的用途。因此，目标 3 的所有分析都将通过全基因组表达分析来完成，以确定假设基因的表达，并提供满足分类器新成员的训练和测试标准的其他基因探针组的识别。最后一个目标 4 是检验以下假设：肿瘤来源的 TGFBetal 表达是与促进此处观察到的许多预后基因的差异基因表达相关的因素。因此，提出了一个程序来验证、扩展和理解基因谱机制的一个重要方面，这些基因谱仅基于基质表达以及具有早期检测和预后潜力的基因子集进行诊断。提出了与 EDRN 进行关键交互以补充样本并作为盲态验证站点。预期的测试开发已计划好，此处生成的所有关键数据都将在 CLIA 实验室中开发。

DESCRIPTION (provided by applicant): We have developed methods for the determination of cell-specific gene expression for the four major cell types that compose prostate cancer including stroma cells. These studies reveal that hundreds of significant differential expressions distinguish normal stroma from tumor-adjacent stroma. These differences have been exploited to develop a Diagnostic Classifier based on genes expressed nearly exclusively in stroma. The Diagnostic Classifier accurately identifies the presence or absence of tumor in over 300 independent prostate cancer test sets including subsets containing on1 of microarray data based one. Further a subset of the Classifier genes accurately identifies "reactive" stroma vs. normal stroma that is associated with poor outcome indicating prognostic potential. We hypothesize that this stroma-based Classifier may be applied to negative clinical biopsies of patients 1 slatted for repeat biopsy to determine the presence of tumor thereby providing Early Detection 6 - 12 months ahead of the repeat biopsy results. Since most of the annual one million biopsies are negative and ~190,000 are scheduled for repeat biopsy, this is an enormous unmet need with no accepted biomarkers for diagnosis and/or early detection for negative biopsy cases. In Aims 1 and 2 validations with independent test array data and validation with LCM-prepared samples are proposed. Aim 3 is a prospective clinical study of new patients consented via the UCI SPECS consortium and SPORE at Northwestern University to collect negative biopsies of patients slatted for repeat biopsy. The repeat biopsy results are used to test the hypothesis that 72 predicted probe sets are valid Diagnostic, Early Detection, and Prognostic biomarkers. A clinical prospective study of Early Detection is possible since the analysis for each consented patient is completed at the time of the repeat biopsy. This is a novel and rare use of negative biopsy material. Therefore all analyses of Aim 3 will be done by genome wide expression analysis to determine the expression of the hypothetical genes and provide for identification of other probe sets of genes that meet the training and testing criteria for new members of the Classifier. The last Aim, 4, is to test the hypothesis that tumor-derived TGFBetal expression is a factor that is associated with promoting differential gene expression of many of the prognostic genes observed here. Thus a program to validate, extend, and understand an important aspect of mechanism of a profile of genes that are diagnostic based on stroma expression alone with subsets of genes with Early Detection and Prognostic potential is proposed. Key interactions with the EDRN for sample supplementation and as a site of a blinded validation are proposed. The anticipated test development is planned and all key data generated here will be developed in a CLIA lab.