Growth Factors and Lethal Prostate Cancer Signature

描述（由申请人提供）：前列腺癌（PCa）的核心问题是在诊断时识别潜在的致命癌症，并确定区分致命疾病和惰性疾病的原因和潜在机制。采用仅限病例的设计，我们将通过比较随后致死性PCa病例的肿瘤组织的RNA表达谱，与没有已知致死性疾病的男性肿瘤组织的RNA表达谱，开发潜在致死性PCa的分子特征。与哈佛大学/麻省理工学院布罗德研究所的研究人员合作，我们建议应用一种新颖但经过验证的高通量分析技术，使用24,000个基因平台来评估档案肿瘤组织中的RNA表达。我们之前的工作提供了胰岛素样生长因子（IGF）系统在PCa风险和进展中的关键作用的证据。我们已经收集了一个广泛的前瞻性临床和血清学数据库，包括长达26年的随访。在许多提供诊断前血液样本的病例中，已经检测了种系多态性和血浆中IGF轴的水平。我们现在建议将这项工作扩展到额外的IGF/胰岛素成分，包括种系变异和肿瘤表达，与PCa进展和死亡率有关。采用仅病例设计，我们将评估循环生物标志物并标记IGF/胰岛素轴上的种系多态性，将致死病例与没有已知致死疾病的男性进行比较。我们还将评估与致死性PCa相关的PCa组织中IGF/胰岛素信号的改变（RNA和蛋白质表达），并将血浆和遗传生物标志物与肿瘤组织数据相结合，以阐明失调的基因通路。基于有趣的初步数据，我们将表征肿瘤样本中常见基因易位、TMPRSS2:ERG融合的存在，并研究融合阳性肿瘤在暴露于高水平的IGF/胰岛素信号时是否更有可能进展。该研究将在医师健康研究（PHS）和卫生专业人员随访研究（HPFS）队列中进行，研究对象为1982-2008年诊断的PCa病例。我们已经建立了1,600例PCa肿瘤库（178例死亡）用于组织标记分析，并正在构建高密度组织微阵列用于定量免疫组织化学和FISH分析。我们将测量血浆中循环生物标志物的水平（N=1,881），并分析提取DNA的snp （N=2,281）。所有前列腺癌患者的治疗、PSA升高、转移和死亡原因的信息被集中随访，随访至2012年。RNA表达数据将极大地增强我们对IGF/胰岛素依赖和独立通路对致死性PCa发展的影响的理解，这将有助于设计靶向治疗和预防策略。大多数关于前列腺癌进展的研究都是基于PSA水平的升高。我们的建议的一个主要优势是我们使用了最具临床相关性的终点，致命性PCa。从致死性前列腺癌的分子特征中，我们可以识别出少数高度预测性的标记物，这些标记物最终可以在活检样本中进行评估。因此，研究结果可以转化为临床实践，使临床医生能够自信地确定哪些肿瘤需要积极治疗。利用这些丰富的现有数据和基础设施资源，可以进行高成本效益的研究，并且具有长期合作记录的跨学科合作者团队将确保该项目的成功。

DESCRIPTION (provided by applicant): A central issue in prostate cancer (PCa) is to recognize potentially lethal cancer at diagnosis, and to identify the causes and underlying mechanisms that distinguish lethal from indolent disease. Using a case-only design, we will develop a molecular signature for potentially lethal PCa by comparing the RNA expression profiles of tumor tissue from subsequently lethal PCa cases to tumor tissue from men without known lethal disease. Collaborating with researchers at the Broad Institute of Harvard University/MIT, we propose to apply a novel but proven high-throughput profiling technology to assess RNA expression in archival tumor tissue using a 24,000 gene platform. Our previous work provided converging evidence of a key role of the insulin-like growth factor (IGF) system in PCa risk and progression. We have already assembled an extensive prospective clinical and serological database on PCa with up to 26 years of follow-up. Germline polymorphisms and plasma levels of the IGF axis have been assayed in many cases who provided a prediagnostic blood sample. We now propose to extend this work with additional IGF/insulin components, including germline variations and tumor expression, in relation to PCa progression and mortality. Using a case-only design, we will assess circulating biomarkers and tagging germline polymorphisms in the IGF/insulin axis, comparing lethal cases to men without known lethal disease. We will also assess alterations of IGF/insulin signaling in PCa tissue (RNA and protein expression) in relation to fatal PCa, and will integrate plasma and genetic biomarkers with tumor tissue data to illuminate gene pathways that are dysregulated. Based on intriguing preliminary data, we will characterize tumor samples for presence of the common gene translocation, the TMPRSS2:ERG fusion, and address whether fusion positive tumors are more likely to progress when exposed to high levels of IGF/insulin signaling. The research will be conducted in the Physicians' Health Study (PHS) and Health Professionals Follow-up Study (HPFS) cohorts among incident PCa cases diagnosed from 1982-2008. We have assembled a PCa tumor repository of 1,600 cases (178 fatal) for tissue marker assays and are constructing high-density tissue microarrays for quantitative immunohistochemistry and FISH assays. We will have levels of circulating biomarkers measured in plasma (N=1,881) and SNPs assayed on extracted DNA (N=2,281). All men with PCa are followed intensively for information on treatment, PSA rise, metastases and cause of death with complete follow-up through 2012. The RNA expression data will greatly enhance our understanding of the influence of the IGF/insulin dependent and independent pathways on development of lethal PCa, which will aid in designing targeted therapy and prevention strategies. Most studies of PCa progression are based on elevations of PSA levels. A major strength of our proposal is that we use the most clinically relevant endpoint, lethal PCa. From the molecular signature of lethal PCa, we can identify a small number of highly predictive markers that could be ultimately assessed in biopsy samples. Thus, the findings can be translated to clinical practice, enabling clinicians to identify with confidence which tumors require aggressive therapy. Use of this rich resource of existing data and infrastructure permits a highly cost-efficient study, and the cross-disciplinary team of collaborators with a longstanding record of working together will ensure success of this project. PUBLIC HEALTH RELEVANCE: Prostate cancer is among the most common cancers in men, and a major cause of cancer death. A central problem is that with PSA screening, many men are diagnosed with a cancer that would not cause them harm, and they undergo therapy unnecessarily. We propose to use an exciting innovative technology to identify a molecular tumor signature to distinguish prostate cancers that are indolent, and can safely be left untreated, from those that are potentially lethal and require aggressive therapy. We also plan to extend our work to identify the causes of lethal prostate cancer as they relate to the growth factor pathway.