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.

抽象的 黑人是世界上侵略性前列腺癌（PC）的最高风险之一。即使是平等的 访问设置，我们发现差异持续存在，为这些差异提供了生物学基础。确实，黑色 与白色PC相比，PC具有基因融合（例如TMPRSS2-ERG）的可能性较小。但是，详细的基因组 或从未进行过针对这些差异的黑白PC的表观基因组分析。 在初步但大规模的基因表达分析中，黑色（n = 305）和白色（n = 238）男性 接受手术，我们发现了种族多种不同激活的途径。当通过分子分层 亚型由我们的团队开发，许多差异仅在某些亚型而不是其他亚型中出现，而是在争论 种族对基因表达差异的任何分析都必须解释分子亚型的差异。 根据这些数据，我们获得了R01赠款（MPI Freeman/Freedland），以进一步分析 转录组数据以及新型主调节器（MR）转录因子的表征我们 neCut2被确定为PC中很重要，尤其与黑色PC相关。在工作期间 r01，我们发现，当肿瘤是基于高表达的高表达时，该途径更活跃 在黑色PC中，这对黑人男人来说是丰富的。因此，这是一种富含肿瘤生物的新型管道 与黑人最相关。鉴于黑人男性的许多顶级活动途径与炎症有关， 我们建议研究“发炎”肿瘤（炎症途径高激活的肿瘤） 我们假设一组不同的MRS在黑人与白人的PC中活跃，并且这些MRS Drive 信号通路和细胞过程的差异阵列。表征这些MRS和理解 它们对PC基因表达的影响对于确定富含黑人或白人男性的新靶标至关重要。 在Tamukong博士的这一一年的多样性补充中，我们提出了一个具体目标：确定与种族相关的目的 基因表达签名特定于“发炎”肿瘤（即炎症激活高的肿瘤 途径）并确定其上游主调节驱动程序。 为了实现，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 分析以定义哪些肿瘤“发炎”。在这些肿瘤中，我们将：1。确定不同表达的 种族基因； 2。按种族确定顶部的不同调节途径； 3。鉴定竞赛的关键MRS。 尽管我们和其他人的工作发现黑色PC更可能过表达炎症 途径，没有研究分析了这些“发炎”中的差异基因表达模式 肿瘤也不确定在这些肿瘤中驱动转录网络的MRS。我们的论文 医学使用了与本研究相同的管道，该管道确定了一个新颖的MR和潜在PC目标 （OneCut2）。我们预计这项研究将确定由富含夫人的MRS管辖的广泛基因表达程序 靶向时，黑人在“发炎”肿瘤中会导致PC健康分布减少。