Growth Factors and Lethal Prostate Cancer Signature

描述(申请人提供)：前列腺癌(PCA)的一个中心问题是在诊断时识别潜在的致命性癌症，并确定区分致命性和惰性疾病的原因和潜在机制。使用仅病例设计，我们将通过比较来自随后致命的PCa病例的肿瘤组织和来自没有已知致命性疾病的男性的肿瘤组织的RNA表达谱，来开发潜在致命的PCa的分子特征。与哈佛大学/麻省理工学院博德研究所的研究人员合作，我们提议应用一种新颖但经过验证的高通量分析技术来评估档案肿瘤组织中的RNA表达，使用24,000个基因平台。我们先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聚合证据。我们已经收集了一个关于前列腺癌的广泛的前瞻性临床和血清学数据库，并进行了长达26年的随访。在提供诊断前血液样本的许多病例中，已经对IGF轴的种系多态和血浆水平进行了检测。我们现在建议用更多的IGF/胰岛素成分来扩展这项工作，包括生殖系变异和肿瘤表达，与PCa进展和死亡率有关。使用仅病例设计，我们将评估循环生物标记物和标记胰岛素样生长因子/胰岛素轴的胚系多态，将致死性病例与未发现致死性疾病的男性进行比较。我们还将评估与致死性前列腺癌相关的PCa组织中IGF/胰岛素信号的变化(RNA和蛋白质表达)，并将血浆和遗传生物标记物与肿瘤组织数据相结合，以阐明失调的基因途径。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的存在，TMPRSS2：ERG融合，并解决融合阳性肿瘤是否更有可能在暴露于高水平的IGF/胰岛素信号时进展。这项研究将在医师健康研究(PHS)和卫生专业人员后续研究(HPFS)队列中进行，研究对象是1982-2008年间确诊的PCA事件病例。我们已经组装了1,600例(178例致命)的PCA肿瘤存储库，用于组织标志物分析，并正在构建用于定量免疫组织化学和FISH分析的高密度组织微阵列。我们将在血浆中测量循环生物标志物的水平(N=1,881)，并在提取的DNA上检测SNP(N=2,281)。所有患有前列腺癌的男性都被密切关注，以获得有关治疗、PSA上升、转移和死亡原因的信息，并全面随访到2012年。RNA表达数据将大大加深我们对IGF/胰岛素依赖和独立途径在致死性PCa发生中的影响的理解，这将有助于设计有针对性的治疗和预防策略。大多数关于前列腺癌进展的研究都是基于PSA水平的升高。我们建议的一个主要优点是我们使用了临床上最相关的终点--致死性前列腺癌。从致死性前列腺癌的分子特征中，我们可以确定少数高预测性的标记物，这些标记物最终可以在活检样本中进行评估。因此，这些发现可以转化为临床实践，使临床医生能够自信地识别哪些肿瘤需要积极治疗。利用现有数据和基础设施的丰富资源可以进行高成本效益的研究，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。 公共卫生相关性：前列腺癌是男性最常见的癌症之一，也是癌症死亡的主要原因。一个核心问题是，通过PSA筛查，许多男性被诊断出患有不会对他们造成伤害的癌症，他们接受了不必要的治疗。我们建议使用一种令人兴奋的创新技术来识别分子肿瘤特征，以区分那些惰性的、可以安全地不治疗的前列腺癌与那些潜在的致命的、需要积极治疗的前列腺癌。我们还计划扩大我们的工作，以确定致命性前列腺癌的原因，因为它们与生长因子途径有关。

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.