Racial Differences in Prostate Cancer Molecular Subtyping

前列腺癌分子亚型的种族差异

• 批准号: 10381279
• 负责人: Stephen Jay Freedland
• 金额: $ 8.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381279
• 关键词: Accounting; African; Bioinformatics; Biological; Cell physiology; Data; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Fusion; Genes; Genetic Transcription; Genomics; Grant; Inflammatory; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Native-Born; Nature; Operative Surgical Procedures; Paper; Parents; Pathway interactions; Pattern; Race; Signal Pathway; TMPRSS2 gene; Tissue-Specific Gene Expression; Tumor Biology; Tumor Subtype; Work; base; black men; cancer gene expression; cancer health disparity; differential expression; epigenomics; high risk; men; molecular subtypes; mortality risk; novel; overexpression; programs; racial difference; transcription factor; transcriptomics; tumor

ABSTRACT Black men have one of the highest risks of aggressive prostate cancer (PC) in the world. Even in an equal access setting, we found disparities persist, arguing for a biological basis for these disparities. Indeed, Black PCs are less likely than White PCs to have gene fusions such as TMPRSS2-ERG. However, a detailed genomic or epigenomic profiling of Black and White PCs accounting for these differences has never been performed. In a preliminary, but large-scale gene expression analysis of PCs in Black (n=305) and White (n=238) men undergoing surgery, we found multiple differentially activated pathways by race. When stratified by a molecular subtype developed by our team, many differences were only seen in certain subtypes and not others, arguing that any analysis of gene expression differences by race must account for differences in molecular subtyping. Based upon these data, we received an R01 grant (MPI Freeman/Freedland) to perform further analysis of the transcriptomic data along with characterization of a novel master regulator (MR) transcription factor we identified as being important in PC and particularly relevant for Black PCs, ONECUT2. During the work for this R01, we found that when tumors were selected based upon high expression of a pathway that was more active in Black PCs, this enriched for Black men. As such, this is a novel pipeline to enrich for tumor biologies that are most relevant for Black men. Given that many of the top active pathways in Black men were inflammatory related, we propose to study “inflamed” tumors (tumors with high activation of inflammatory pathways) We hypothesize a distinct set of MRs are active in PCs from Black vs. White men and that these MRs drive a differential array of signaling pathways and cellular processes. Characterizing these MRs and understanding their impact on PC gene expression are crucial to identify novel targets enriched in Black or White men. In this one-year diversity supplement to Dr. Tamukong, we propose one specific Aim: Identify race-associated gene expression signatures specific to “inflamed” tumors (i.e. tumors with high activation of inflammatory pathways) and determine their upstream master regulator drivers. To accomplish, we will use the Durham VA transcriptomic data and conducted a detailed bioinformatic analysis to define which tumors are “inflamed”. Within these tumors, we will: 1. Identify differentially expressed genes by race; 2. Determine the top differentially regulated pathways by race; 3. Identify key MRs by race. Despite the fact that work from us and others found Black PCs are more likely to over-express inflammatory pathways, no study has analyzed the differential gene expression patterns specifically within these “inflamed” tumors nor determined the MRs that drive the transcriptional network within these tumors. Our paper in Nature Medicine used the identical pipeline as in this study, which identified a novel MR and potential PC target (ONECUT2). We expect this study will identify broad gene expression programs governed by MRs enriched in Black men within “inflamed” tumors that when targeted, will lead to reduced PC health disparities.

摘要 黑人男性是世界上侵袭性前列腺癌（PC）风险最高的人群之一。即使在一个平等的 在获取环境中，我们发现差异仍然存在，认为这些差异有生物学基础。确实，布莱克 与白色PC相比，PC不太可能具有基因融合，如TMPRSS 2-ERG。然而，详细的基因组 或对黑人和白色PC进行表观基因组分析来解释这些差异的方法从未被实施过。 在对黑人（n=305）和白色（n=238）男性PC进行的初步但大规模的基因表达分析中， 通过手术，我们发现了多种不同种族的激活途径。当被一种分子分层时 我们的团队开发的亚型，许多差异只在某些亚型中看到，而不是其他亚型， 任何种族基因表达差异的分析都必须考虑到分子亚型的差异。 基于这些数据，我们获得了R 01资助（MPI Freeman/Freedland），以进一步分析 转录组学数据沿着一种新主调节因子（MR）转录因子的特征， 在PC中被认为是重要的，特别是与黑色PC相关，ONECUT 2。在这项工作中， R 01，我们发现，当肿瘤是基于一个更活跃的途径的高表达进行选择时， 在黑人电脑中，这丰富了黑人。因此，这是一个新的管道，以丰富肿瘤生物制剂， 与黑人男性最相关。考虑到黑人男性中许多最活跃的通路与炎症有关， 我们建议研究“炎症”肿瘤（炎症通路高度活化的肿瘤） 我们假设一组不同的MR在黑人与白色男性的PC中是活跃的，并且这些MR驱动 一系列不同的信号通路和细胞过程。描述这些MR并了解 它们对PC基因表达的影响对于鉴定在黑人或白色男性中富集的新靶点是至关重要的。 在这一年的多样性补充Tamukong博士，我们提出了一个具体的目标：确定种族相关的 特异于“发炎”肿瘤（即炎性细胞高度活化的肿瘤）的基因表达特征 通路）并确定它们的上游主调节器驱动器。 为了完成，我们将使用达勒姆VA转录组数据，并进行了详细的生物信息学 分析以确定哪些肿瘤是“发炎的”。在这些肿瘤中，我们将：1。鉴定差异表达 种族基因; 2.通过种族确定最高的差异调节途径; 3.按种族确定关键MR。 尽管我们和其他人的研究发现，黑人更有可能过度表达炎症， 通路，没有研究分析了差异基因表达模式，特别是在这些“发炎” 也没有确定驱动这些肿瘤内转录网络的MR。我们在Nature上的论文 医学使用与本研究相同的管道，确定了新的MR和潜在的PC靶点 （ONECUT2）.我们希望这项研究将确定广泛的基因表达程序，这些程序由富含 黑人男性在“发炎”肿瘤，当有针对性，将导致减少PC健康的差距。