Molecular Signatures of Lethal an Indolent Prostate Cancer

21世纪初医学面临的主要挑战之一是将 人类基因组进入患者的医疗管理，从而产生更准确的诊断和 以机制为基础的治疗部署。没有任何地方比治疗男性更迫切需要这种需求了 患有前列腺癌。前列腺癌是导致死亡和发病的一个主要原因，但有大量的男性 据信，即使在没有治疗的情况下，肿瘤也是惰性的。因此，许多男人都会得到 不必要的治疗及其随之而来的影响，另一些人尽管积极治疗，但仍死于疾病。我们 假设CAP的自然历史的变异性是由迄今未被认识到的 这种疾病的分子异质性。因此，我们建议在这里识别一个基因表达特征 这就是懒惰与致命疾病的区别。 该项目有三个具体目标： 目标1：收集、登记和处理存档的福尔马林固定石蜡包埋(FFPE)样本 瑞典观察等待(WW)队列，临床随访长达30年。 目的2：在警觉等待的FFPE上开发致命性和惰性前列腺癌的分子标记 使用Illumina表达阵列平台的样本，该平台具有6000多个专门为 分子特征发现。 目标3：验证AIM 2中未使用的瑞典WW案例上的签名，并测试这些签名是否存在 来自医生健康研究(PHS)的肿瘤样本(n=100)的概况。 在这项提案的结论中，我们预计已经发现并验证了 前列腺癌的结果适合于进一步的临床发展。为了实现这些目标，我们 组建了一支多学科的调查团队，有着长期的合作记录，并与 在前列腺癌的临床、病理和流行病学方面的专门知识， 基因组学技术的开发和部署，以及高级计算和统计 分析。

One of the main challenges for medicine in the early part of 21st century is to incorporate knowledge of the human genome into the medical management of patients, thereby yielding more precise diagnoses and mechanism-based deployment of therapy. Nowhere is this need more pressing than in the treatment of men with prostate cancer. Prostate cancer is a major cause of death and morbidity, yet large numbers of men are believed to harbor tumors that are indolent even in the absence of therapy. As such, many men receive unnecessary treatment with its attendant effects, and others die of disease despite aggressive therapy. We hypothesize that the variability in the natural history of CaP is determined by heretofore unrecognized molecular heterogeneity of the disease. We therefore propose here to identify a gene expression signature that distinguishes indolent from lethal disease. This Project has 3 Specific Aims: Aim 1: Collect, register, and process archival formalin-fixed paraffin embedded (FFPE) samples from the Swedish Watchful Waiting (WW) cohorts with up to 30 years clinical follow up. Aim 2: Develop molecular signatures of lethal and indolent prostate cancer on the Watchful Waiting FFPE samples using an Illumina expression array platform with over 6000 genes developed specifically for molecular signature discovery. Aim 3: Validate the signatures on Swedish WW cases not used in Aim 2 and test for the presence of these profiles in tumor samples (n=100) from the Physicians' Health Study (PHS). At the conclusion of this proposal, we expect to have discovered and validated molecular predictors of prostate cancer outcome that are appropriate for further clinical development. To accomplish these goals, we have assembled a multidisciplinary team of investigators with a long track record of collaboration, and with particular expertise in the clinical, pathological and epidemiological aspects of prostate cancer, in the development and deployment of genomics technologies, and in advanced computational and statistical analysis.