Genetic Signatures Underlying Prostate Cancer Metastasis in AfricanAmericans

非裔美国人前列腺癌转移的基因特征

• 批准号: 9092899
• 负责人: MEZBAH U. FARUQUE
• 金额: $ 22.99万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9092899
• 关键词: Adopted; Affect; African; African American; Arts; Automobile Driving; Award; Bioinformatics; Biological; Biology; Cancer Biology; Cancer Patient; Cancerous; Categories; Cessation of life; Clinical; Clonal Evolution; Coupled; DNA; DNA Sequence; DNA Sequence Alteration; Data; Diagnosis; Discipline; Disease; Disease Progression; Dissection; Disseminated Malignant Neoplasm; Distant Metastasis; Early Diagnosis; Ethnic Origin; Funding; Generations; Genes; Genetic; Genomics; Glean; Goals; Grant; In Vitro; Incidence; Individual; Indolent; Investigation; Lead; Left; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Metastatic Prostate Cancer; Metastatic to; Molecular; Monitor; Morbidity - disease rate; Mutate; Mutation; National Heart, Lung, and Blood Institute; Nature; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathologist; Pathology; Pathway interactions; Patients; Phase; Population; Populations at Risk; Primary Neoplasm; Prostate; Recurrence; Resolution; Role; Seeds; Somatic Mutation; Specimen; Statistical Data Interpretation; Structure of base of prostate; System; Technology; Testing; TimeLine; Tissues; United States; United States National Institutes of Health; Universities; Validation; base; cancer biomarkers; cancer classification; cancer diagnosis; cancer genome; cancer genomics; caucasian American; cost effective; curative treatments; design; disability; exome sequencing; experience; follow-up; genetic signature; genome sequencing; insight; knock-down; men; metastatic process; molecular targeted therapies; mortality; next generation sequencing; overexpression; prostate cancer cell; public health relevance; racial difference; research study; risk variant; screening; specific biomarkers; therapy development; tool; treatment response; tumor; tumorigenesis; verification and validation; whole genome

 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.

 描述（由申请人提供）：前列腺癌（PCa）是美国男性中最常见的非皮肤癌。现在已经确定，PCa的发病率和相关死亡率和发病率显示出种族特异性差异，非裔美国人受到不成比例的影响。与PCa患者管理相关的一个主要挑战是疾病进展的可变性和通常惰性。很难预测被诊断患有PCa的男性如果不进行治疗或采用比手术更具侵略性的方法进行治疗是否会发展为侵袭性癌症。大多数PCa的死亡和残疾可归因于疾病的转移阶段，目前还没有治愈性治疗。PCa转移的分子和细胞基础仍然知之甚少，从体细胞遗传学改变获得的多次命中被认为是重要的促成因素。该项目的中心假设是，比较来自同一患者的正常、原发性和转移性癌性前列腺组织可以识别驱动PCa转移的体细胞突变。为了验证这一假设，我们提出了本研究的两个具体目标：（i）对来自20名非洲裔美国人患者的正常、原发性肿瘤和转移性前列腺癌组织进行全外显子组测序，以鉴定体细胞风险变体，绘制突变基因并鉴定转移候选者;以及（ii）对从具体目标1中鉴定的两个排名靠前的基因进行体外功能表征。 使用强制过表达和敲低方法来评估它们在驱动PCa转移中的机制影响。这项研究的结果将导致我们目前对PCa转移的遗传基础的理解的进步。从本研究结果中鉴定的PCa转移特异性生物标志物具有临床上用于筛选、诊断或监测PCa进展并指导分子靶向治疗或评估治疗反应的潜力。这项研究的结果不仅可以为非洲裔美国人提供有用的信息，而且还可以为这种疾病提供更普遍的见解。