Growth Factors and Lethal Prostate Cancer Signature

描述（由申请人提供）：前列腺癌（PCa）的一个核心问题是在诊断时识别潜在致命的癌症，并确定区分致命疾病和惰性疾病的原因和潜在机制。使用仅限病例的设计，我们将通过比较随后致死 PCa 病例的肿瘤组织与无已知致命疾病的男性肿瘤组织的 RNA 表达谱，开发潜在致命 PCa 的分子特征。我们与哈佛大学/麻省理工学院博德研究所的研究人员合作，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一致的证据，证明胰岛素样生长因子 (IGF) 系统在 PCa 风险和进展中发挥着关键作用。我们已经建立了一个广泛的前列腺癌前瞻性临床和血清学数据库，并进行了长达 26 年的随访。在许多提供诊断前血样的病例中，已对种系多态性和 IGF 轴血浆水平进行了测定。我们现在建议用额外的 IGF/胰岛素成分来扩展这项工作，包括与 PCa 进展和死亡率相关的种系变异和肿瘤表达。使用仅限病例的设计，我们将评估循环生物标志物并标记 IGF/胰岛素轴中的种系多态性，将致命病例与没有已知致命疾病的男性进行比较。我们还将评估 PCa 组织中 IGF/胰岛素信号传导（RNA 和蛋白质表达）与致命性 PCa 相关的变化，并将血浆和遗传生物标志物与肿瘤组织数据整合，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是否存在常见基因易位（TMPRSS2:ERG 融合），并解决融合阳性肿瘤在暴露于高水平 IGF/胰岛素信号传导时是否更有可能进展。该研究将在医生健康研究 (PHS) 和健康专业人员随访研究 (HPFS) 队列中对 1982 年至 2008 年诊断出的前列腺癌病例进行。我们已经建立了一个包含 1,600 例（其中 178 例死亡）的 PCa 肿瘤库，用于组织标志物测定，并正在构建用于定量免疫组织化学和 FISH 测定的高密度组织微阵列。我们将测量血浆中循环生物标志物的水平 (N=1,881) 并分析提取的 DNA 中的 SNP (N=2,281)。所有患有 PCa 的男性都受到集中随访，以获取有关治疗、PSA 升高、转移和死亡原因的信息，并在 2012 年进行完整随访。RNA 表达数据将极大地增强我们对 IGF/胰岛素依赖和独立途径对致命性 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 PCa 进展研究都是基于 PSA 水平的升高。我们提案的一个主要优势是我们使用临床上最相关的终点，致死性 PCa。从致死性 PCa 的分子特征中，我们可以识别出少数可最终在活检样本中进行评估的高度预测标记物。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极具成本效益的研究，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。 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，并且他们接受了不必要的治疗。我们建议使用一项令人兴奋的创新技术来识别分子肿瘤特征，以区分惰性且可以安全地不进行治疗的前列腺癌与可能致命且需要积极治疗的前列腺癌。我们还计划扩展我们的工作，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.