Molecuar Sub-typing of Prostate Cancer Based on Recurrent Gene Fusions

描述（由申请人提供）：采用生物信息学方法分析前列腺癌基因表达谱，我们在大多数前列腺癌中发现了复发性基因融合/易位（Tomlins等人，Science 2005）。具体来说，我们确定了TMPRSS2的雄激素调节元件融合到ETS家族的转录因子中，包括ERG、ETV1、ETV4和ETV5。与血液学恶性肿瘤类似，在前列腺癌中发现的基因融合/易位可能代表了疾病的病理特征生物标志物和分子亚型。在这个应用中，我们计划将我们的努力集中在表征这类新的基因融合生物标志物上。本课题组和其他人的初步工作表明，基因融合的分子亚型和转录变体可能与前列腺癌的临床亚型有关。这项应用的中心假设是，基于基因融合和变异的分子亚型将是临床局限性前列腺癌侵袭潜力的有用预测因子，从而指导治疗。鉴于此，我们提出以下目标：具体目标1：发现和提名新的前列腺癌分子亚型。特异性目的2：在根治性前列腺切除术队列中，描述前列腺癌分子亚型与临床结局和/或疾病侵袭性的关系。具体目标3。利用前列腺穿刺活检样本表征前列腺癌分子亚型与临床结果和/或疾病侵袭性的关系。公共卫生相关性：项目叙述：基因融合在一起的发现是对前列腺癌理解的重大进步。这项提议是关于使用这些“基因融合”来确定预后类别，以改善前列腺癌患者的治疗方法。

DESCRIPTION (provided by applicant): Employing a bioinformatics approach to analyze prostate cancer gene expression profiles, we identified recurrent gene fusions/translocations in the majority of prostate cancers (Tomlins et al, Science 2005). Specifically, we identified the androgen regulatory elements of TMPRSS2 fused to the members of the ETS family of transcription factors including ERG, ETV1, ETV4 and ETV5. Analogous to hematological malignancies, gene fusions/translocations identified in prostate cancer may represent pathognomonic biomarkers and molecular sub-types of disease. In this application, we plan to focus our efforts on characterizing this new class of gene fusion biomarkers. Preliminary work done by our group and others suggest that molecular subtypes as well as transcript variants of gene fusions may be associated with clinical sub-types of prostate cancer. The central hypothesis of this application is that molecular sub-types based on gene fusions and variants will be useful predictors of the aggressive potential of clinically localized prostate cancer and thus guide treatment. Given this, we propose the following Aims: Specific Aim 1: Discovery and nomination of novel molecular sub-types of prostate cancer. Specific Aim 2: Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease in a radical prostatectomy cohort. Specific Aim 3. Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease using prostate needle biopsy samples. PUBLIC HEALTH RELEVANCE: Project Narrative: The discovery of genes fused together is a major advancement in the understanding of prostate cancer. This proposal is about using these "gene fusions" to identify prognostic categories to improve approaches to the treatment of prostate cancer patients.