Genetic Signatures Underlying Prostate Cancer Metastasis in AfricanAmericans

 描述(申请人提供)：前列腺癌(PCa)是美国男性中最常见的非皮肤癌。现在公认的是，前列腺癌的发病率和相关的死亡率和发病率显示出种族差异，非裔美国人受到的影响不成比例。与PCa患者管理相关的一个主要挑战是疾病进展的多变和通常缓慢的性质。很难预测被诊断患有前列腺癌的患者是否会患上侵袭性癌症，如果不进行治疗，或者采用比手术侵袭性更小的方法进行治疗。大多数前列腺癌的死亡和残疾可归因于疾病的转移阶段，目前还没有根治方法。前列腺癌转移的分子和细胞基础仍不清楚，体细胞遗传改变获得的多个命中被认为是重要的促成因素。该项目的中心假设是，比较同一患者的正常、原发和转移的前列腺癌组织可以确定驱动前列腺癌转移的体细胞突变。为了验证这一假设，我们提出了这项研究的两个具体目标：(I)对来自20名非裔美国人的正常、原发肿瘤和转移性前列腺癌组织进行全外显子组测序，以识别躯体风险变量，定位突变基因并确定转移候选基因；以及(Ii)对从特定目标1确定的两个排名靠前的基因进行体外功能鉴定。 使用强制过表达和基因敲除方法来评估它们在驱动PCa转移中的机制影响。这项研究的结果将促进我们目前对前列腺癌转移的遗传学基础的理解。从本研究结果中确定的PCa转移特异性生物标志物有可能用于临床筛查、诊断或监测PCa的进展，指导分子靶向治疗或评估治疗反应。这项研究的发现不仅可能为非裔美国人提供有用的信息，还可以为这种疾病提供更普遍的见解。

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common noncutaneous cancer diagnosed in men in the United States. It is now well established that the incidence and associated mortality and morbidity from PCa shows ethnicity specific disparity, African Americans being disproportionately affected. One major challenge related to management of PCa patients is the variable and often indolent nature of the disease progression. It is difficult to predict whether men diagnosed with PCa will develop aggressive cancer if left untreated or treated with an approach less aggressive than surgery. Most deaths and disabilities from PCa are attributable to the metastatic phase of the disease, for which currently there is no curative therapy. The molecular and cellular underpinnings of PCa metastasis remain poorly understood, multiple-hits acquired from somatic genetic alterations are considered to be important contributing factor. The central hypothesis of this project is that comparing normal, primary and metastatic cancerous prostate tissues from the same patient can identify somatic mutations driving metastasis of PCa. To test this hypothesis, we propose two specific aims for this study: (i) to perform whole exome sequencing of normal, primary tumor and metastatic prostate cancer tissue from 20 African American patients to identify somatic risk variants, mapping the mutated genes and identifying candidates for metastasis; and (ii) To perform in vitro functional characterization of two top-ranked genes identified from specific aim 1 using forced overexpression and knockdown approaches to evaluate their mechanistic impact in driving PCa metastasis. Results from this study will lead to the advancement in our current understanding on the genetic underpinnings of PCa metastasis. PCa metastasis specific biomarkers identified from the results of this study have the potential to be used clinically to screen for, diagnose or monitor the progression of PCa and to guide molecular targeted therapy or assess therapeutic response. Findings from this study may not only be usefully informative for African Americans, but can also provide more generalizable insights into this disease.