Racial Differences in Prostate Cancer Molecular Subtyping

非裔美国人(AA)男性患前列腺癌(PC)的风险最高。他们呈现的是 晚期疾病，预后比高加索(CA)男性更差。AAPC的基因组学一直以来都是 与CA PC相比，这方面的研究严重不足。目前尚不清楚致癌途径是否会在一场竞赛中驱动PC- 敏感的方式，以及如何针对这类途径。我们最近开发并报道了一部小说 PC分类的算法，我们认为这比以前的方法有了很大的进步。 我们发现，通过单独分析转录组数据，大多数PC可以被分配到仅有的三部小说中的一部 亚型，命名为PCS1(管腔)、PCS2(管腔)和PCS3(基础)。在10多个独立的 队列中，PCS1亚型表现出最差的临床结果，包括在低Gleason的肿瘤中 得分。PCS1和PCS3亚型在抗去势PC(CRPC)中过度表达。基因组学， AA PC的转录和免疫组织化学研究与PCS1的假设一致 而PCS3亚型在非洲血统男性的PC中比例过高。我们用了这本小说 系统，结合其他计算和实验室方法，以确定一个发育 转录因子ONECUT2(OC2)，它在CRPC的一个子集中似乎是一个“主调节器”。 这种蛋白似乎在PCS1和PCS3亚型中最活跃，因此可能是一个关键的 AA患者肿瘤进展的中介物。OC2似乎可以通过小分子和 因此，在AA患者的攻击性PC的背景下，可能是一个可行的药物靶点。 我们将在这项研究中检验两个假设：假设1)PCS系统可以识别不同的分子 再生障碍性贫血患者的PC特征可用于临床辅助风险分层和识别可操作的 与AA男性相关的靶点；以及假设2)OC2是出现在AA男性PC中的一个可行的药物靶点。在AIM 1)我们将确定PC亚型在AA男性中的分布，并评估他们是否类似地预测 AA和CA患者进展为晚期疾病；1.2)确定在AA中起作用的主要调节蛋白 PCS；以及1.3)确定PCS系统的应用是否可以用于提高预测能力 与癌症相关的预后标志。在目标2中，我们将开发使用根治性前列腺切除术和 AA和CA患者的活检标本以确定哪些肿瘤对OC2靶向最敏感 心理治疗。在目标3中，我们将确定OC2是否是一个可行的药物靶点。 这项研究将是迄今为止在AA PC中进行的最大规模的RNA表达数据综合分析。它 将对这样一种假设进行严格的检验，即指定基因调控和信号的分子机制 AA和CA患者的转导不同。这些研究还将评估一种新的药物靶点，它似乎是一种 许多影响非洲血统男性的个人电脑的核心推动者。

African-American (AA) men exhibit one of the highest risks for prostate cancer (PC). They present with later-stage disease and have worse outcomes than Caucasian (CA) men. The genomics of AA PCs has been dramatically understudied compared to CA PCs. It is unclear whether oncogenic pathways drive PC in a race- sensitive manner, and how such pathways might be targeted. We recently developed and reported on a novel algorithm for classification of PC that we believe represents a significant advance over previous approaches. We found that by analyzing transcriptome data alone, most PCs can be assigned to one of only three novel subtypes, named PCS1 (luminal), PCS2 (luminal), and PCS3 (basal). As validated in over 10 independent cohorts, the PCS1 subtype demonstrates the worst clinical outcome, including in tumors with low Gleason score. The PCS1 and PCS3 subtypes are over-represented in castration-resistant PCs (CRPC). Genomics, transcriptomics, and immunohistochemical studies of AA PCs are consistent with the hypothesis that the PCS1 and PCS3 subtypes are over-represented in PCs arising in men of African ancestry. We have used this novel system, in combination with other computational and laboratory approaches, to identify a developmental transcription factor, ONECUT2 (OC2), which appears to operate as a “master regulator” in a subset of CRPCs. This protein appears to be most active in the PCS1 and PCS3 subtypes, and therefore may be a critical mediator of progression in tumors seen in AA men. OC2 appears targetable with a small molecule and therefore may be a viable drug target in the context of aggressive PCs in AA men. We will test two hypotheses in this study: Hypothesis 1) The PCS system can identify distinct molecular features of PCs from AA men that can be used clinically to aid risk stratification and to identify actionable targets relevant to AA men; and Hypothesis 2) OC2 is a viable drug target in PCs that arise in AA men. In Aim 1 we will 1.1) determine the distribution of PC subtypes in AA men, and assess whether they similarly predict progression to advanced disease in AA and CA men; 1.2) identify master regulator proteins operating in AA PCs; and 1.3) determine whether application of the PCS system can be used to improve the predictive power of cancer-relevant prognostic signatures. In Aim 2 we will develop methods using radical prostatectomy and biopsy specimens from AA and CA men to determine which tumors will be most sensitive to OC2-targeted therapy. In Aim 3 we will determine whether OC2 is a viable drug target. This study will be the largest integrated analysis of RNA expression data ever performed in AA PCs. It will provide a rigorous test of the hypothesis that molecular mechanisms specifying gene regulation and signal transduction differ in AA vs. CA men. These studies will also evaluate a novel drug target that appears to be a central driver of many PCs affecting men of African ancestry.