Molecular Signatures of Lethal and Indolent Prostate Cancer

描述（由申请人提供）：特定目的。前列腺癌（PCA）是一种分子异质性疾病，具有从惰性到高度侵袭性的各种临床谱。PCA的一个晚期表现是进展为神经内分泌表型，这是普遍致命的，平均生存期不到一年。据估计，30%的晚期PCA转化为神经内分泌前列腺癌（NEPC），并可能选择或加速使用雄激素剥夺疗法。随着更有效的激素疗法引入临床竞技场（例如，阿比特龙，MDV 3100），预计NEPC的发生率将升高。我们已经从全基因组DNA和RNA测序中获得了初步数据，这使我们假设NEPC起源于腺癌（AdCa），并且指示性分子事件决定了从激素初始AdCa到致命NEPC的进展。因此，我们提出了3个具体目标来阐明NEPC的关键分子驱动因素。具体目标1：定义与NEPC出现相关的体细胞拷贝数改变。该目的的工作假设是，在神经内分泌去分化的发展之前，存在与NEPC相关的复发性体细胞拷贝数改变（SCNA）。在这个目标的结论，我们将提名多达20个基因的SCNA基因座是经常性的NEPC和不太常见的AdCa与转录支持，表明这些是获得功能（癌基因）或功能丧失（肿瘤抑制）基因。具体目标2：确定NEPC中观察到的突变谱。这个目标的工作假设是，有特定的驱动突变的特点NEPC。在这个目标的最后，我们预计，这些突变和重排的子集有助于神经内分泌去分化。我们预计提名多达20个突变，将适合进一步的分子功能评价。具体目的3确定NEPC基因的功能活性。该目标的工作假设是，目标1-2中指定的基因子集的改变是功能突变的获得或丧失。在本目标的结论中，我们将提名NEPC中存在的多达5个功能活性基因和AdCa的一个子集。我们将立即使用异种移植模型对这些基因进行跟踪，作为另一项资助的一部分（本申请中没有提出动物实验）。我们相信，拟议的研究将使我们对一种高度侵袭性的PCA形式有新的认识。 公共卫生相关性：前列腺癌是最常见的非皮肤癌，也是美国男性癌症死亡的第二大原因，2010年估计有超过31，000人死亡。神经内分泌前列腺癌是本研究的重点，是前列腺癌的一种明确定义的亚型，普遍致命，平均生存期不到一年。神经内分泌分化最常见于晚期前列腺癌和暴露于雄激素剥夺治疗后，并且与不良临床结局相关。据估计，至少30%的晚期前列腺癌转化为雄激素剥夺疗法，并且可能被选择用于雄激素剥夺疗法或通过使用雄激素剥夺疗法加速。随着更有效的激素疗法引入临床竞技场（例如，阿比特龙，MDV 3100），预计神经内分泌前列腺癌的发生率将升高。目前NEPC没有有效的治疗方法，许多患者接受基于铂的化疗（类似于小细胞肺癌）。尽管报道的化疗反应率为50-60%，但大多数NEPC患者在6个月内进展，存活不到一年。神经内分泌前列腺癌是一种研究不足的癌症类型。这是由于临床实践中，除非在特殊情况下，否则不采集晚期前列腺癌。我们提出的研究采取了一种雄心勃勃的方法，从世界各地收集样本，并使用高通量基因组测序来帮助了解这种致命疾病的分子基础。

DESCRIPTION (provided by applicant): Specific Aim. Prostate cancer (PCA) is a molecularly heterogeneous disease with a varied clinical spectrum ranging from indolent to highly aggressive. One late manifestation of PCA is progression to a neuroendocrine phenotype, which is universally lethal with an average survival of less than one year. It is estimated that 30% of late stage PCA transforms to neuroendocrine prostate cancer (NEPC), and potentially selected for or accelerated by the use of androgen deprivation therapies. With the introduction of more potent hormonal therapy into the clinical arena (e.g., Abiraterone, MDV3100), the incidence of NEPC is expected to escalate. We have generated preliminary data from Whole Genome DNA and RNA Sequencing leading us to hypothesize that NEPC arises from adenocarcinoma (AdCa) and that telltale molecular events determine a progression from hormone na¿ve AdCa to lethal NEPC. Therefore, we propose 3 Specific Aims to elucidate the key molecular drivers of NEPC. Specific Aim 1: Define Somatic Copy Number Alterations Associated with the Emergence of NEPC. The working hypothesis of this Aim is that there are recurrent somatic copy number alterations (SCNA) associated with NEPC detectable prior to the development of neuroendocrine de-differentiation. At the conclusion of this Aim, we will nominate up to 20 genes from SCNA loci that are recurrent in NEPC and less common in AdCa with transcriptional support suggesting that these are gain of function (oncogenes) or loss of function (tumor suppressor) genes. Specific Aim 2: Determine Spectrum of Mutations Observed in NEPC. The working hypothesis of this Aim is that there are specific driving mutations that characterize NEPC. At the end of this Aim, we anticipate that a subset of these mutations and rearrangements contribute to neuroendocrine de-differentiation. We anticipate nominating up to 20 mutations that will be appropriate for further molecular functional evaluation. Specific Aim 3 Determine the Functional Activity of NEPC Genes. The working hypothesis of this Aim is that alterations in a subset of the genes nominated in Aims 1-2 are gain or loss of function mutations. At the conclusion of this Aim we will have nominated up to 5 functionally active genes that are present in NEPC and a subset of AdCa. We will immediately follow up on these genes using xenograft models as part of another funded grant (no animal experiments are proposed in this application). We believe that the proposed studies will allow us new insight into a highly aggressive form of PCA. PUBLIC HEALTH RELEVANCE: Prostate Cancer is the most common non-cutaneous cancer and the second leading cause of cancer death in American men with over 31,000 estimated death in 2010. Neuroendocrine prostate cancer, the focus of this study, is a well-defined subtype of prostate cancer that is universally lethal with an average survival of less than one year. Neuroendocrine differentiation is most commonly found in advanced stage prostate cancer and after exposure to androgen deprivation therapy, and is associated with a poor clinical outcome. It is estimated that at least 30% of late stage prostate cancer transform to, and potentially selected for or accelerated by the use of androgen deprivation therapies. With the introduction of more potent hormonal therapy into the clinical arena (e.g., Abiraterone, MDV3100), the incidence of Neuroendocrine prostate cancer is expected to escalate. There is currently no effective therapy for NEPC, and many patients are treated with platinum based chemotherapy (similar to small cell lung cancer). Despite a reported response rate of 50-60% to chemotherapy, most patients with NEPC progress within 6 months and survive less than one year. Neuroendocrine prostate cancer is a highly understudied type of cancer. This is due to clinical practices that do not harvest advanced prostate cancer except under special circumstances. Our proposed study has taken an ambitious approach to gather samples from around the world and use high throughput genome sequecning to help understand the molecular underpinnings of this lethal disease.