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Tracing the origins of chromosomal translocations in prostate cancer

追踪前列腺癌染色体易位的起源

基本信息

批准号：
8531687
负责人：
Ram Shankar Mani
金额：
$ 11.48万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531687
关键词：
5&apos Untranslated Regions Affect Air Androgen Receptor Androgens Antibodies Architecture Binding Biological Assay Carcinoma Cell Cycle Progression Cell Line Cells ChIP-seq Chromatin Chromosomal translocation Coculture Techniques DNA DNA Double Strand Break DNA Sequence Rearrangement Data Data Set Development ERG gene ETS Family Gene Enzyme Activation Etiology Future Gene Expression Profiling Gene Expression Regulation Gene Fusion Genes Genome Genomics Goals Hematologic Neoplasms Human Human Genome Inflammation LNCaP Lead Lentivirus Vector Light Link Malignant Neoplasms Malignant neoplasm of prostate Mediating Mentors Methodology Modeling Mus Mutate Mutation NF-kappa B Noise Oncogene Activation Operative Surgical Procedures PSA screening Pathway interactions Patients Phase Phosphorylation Prevalence Prostate Prostatic Publications Recurrence Regulation Resources Role Signal Transduction Soft Tissue Neoplasms Specificity Suggestion TMPRSS2 gene Technology Testing Tissue Microarray Tissues Up-Regulation activation-induced cytidine deaminase base career cell type cohort genome sequencing genome-wide improved in vivo leukemia/lymphoma macrophage next generation sequencing novel p65 research study sarcoma skills transcriptome sequencing tumor progression

项目摘要

DESCRIPTION (provided by applicant): Chromosomal translocations are a hallmark of cancer progression. These translocations often result in gene fusions, a common mechanism for oncogene activation. Until recently, recurrent gene fusions were predominantly associated with hematological malignancies (leukemias and lymphomas) and soft tissue tumors (sarcomas), but were rarely linked to common epithelial carcinomas. This view changed with the discovery of recurrent gene fusions involving ETS family genes in prostate cancer. Among the ETS family gene fusions, the TMPRSS2-ERG fusions involving the 5'untranslated region of androgen-regulated gene TMPRSS2 with the ERG gene are the most common and found in approximately 50% of prostate cancers. The development of next generation sequencing based approaches like RNA-Seq and paired-end whole-genome sequencing have accelerated the discoveries of gene fusions in prostate cancer. However, the mechanisms underlying the formation and cell type specificities of chromosomal translocations are far from clear. Our proposal aims to bridge the gap between the rapid discovery of chromosomal translocations and our limited understanding of the mechanisms leading to their formation. In our recent study, we demonstrate that androgen signaling induces chromosomal proximity between TMPRSS2 and ERG loci, and facilitates the formation of the TMPRSS2-ERG gene fusion when subjected to an agent that causes DNA double strand breaks. These results provide a conceptual framework for the genesis of gene fusions in human prostate cancer. In specific aim 1, we propose to employ next-generation sequencing to identify genome-wide chromosomal interactions mediated by androgen signaling. The mentor's expertise in throughput technologies will help the candidate acquire the necessary skill-set to accomplish aim 1. Interestingly, we identified novel recurrent mutations in the androgen receptor AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers. Preliminary functional studies on one representative mutation revealed that mutated FOXA1 disrupts androgen signaling and increases proliferation. In specific aim 2, we propose to study the effect of FOXA1 mutations in regulating AR signaling and interactome. Aim 2, a logical extension of aim 1 will be pursued during the independent phase (R00). Accomplishment of these two aims will provide us with a comprehensive understanding of the three dimensional genomic architecture of prostatic cells, how AR regulates this architecture, the influence mutations in AR collaborating factors, and importantly how this impacts the formation of gene fusions. While spatial proximity is necessary for chromosomal translocations, it is not sufficient. DNA breaks synergize with spatial proximity to fuel chromosomal translocations. In specific aim 3, we will study the role of inflammation mediated activation of NF-kB pathway in the formation of DNA breaks and ETS gene fusions in prostate cancer. Successful completion of the aims outlined in this proposal will improve our understanding of the origins of chromosomal translocations in prostate cancer, may have broader implications for understanding and treating cancer and may provide suggestions as to the general etiology of human prostate cancer. These projects have been conceived based on my original ideas. Dr. Chinnaiyan has extended his full support towards my career goals and has encouraged me to take these projects to my independent lab in the future.

描述（由申请人提供）：染色体易位是癌症进展的标志。这些易位通常导致基因融合，这是癌基因激活的常见机制。直到最近，复发性基因融合主要与血液恶性肿瘤（白血病和淋巴瘤）和软组织肿瘤（肉瘤）有关，但很少与常见的上皮癌有关。这种观点随着前列腺癌中涉及ETS家族基因的复发性基因融合的发现而改变。在ETS家族基因融合体中，涉及雄激素调节基因TMPRSS 2的5 '非翻译区与ERG基因的TMPRSS 2-ERG融合体是最常见的，并且在大约50%的前列腺癌中发现。下一代基于测序的方法如RNA-Seq和配对末端全基因组测序的发展加速了前列腺癌中基因融合的发现。然而，染色体易位的形成和细胞类型特异性的机制还远不清楚。我们的建议旨在弥合染色体易位的快速发现和我们对导致其形成的机制的有限理解之间的差距。在我们最近的研究中，我们证明，雄激素信号诱导TMPRSS 2和ERG基因座之间的染色体接近，并促进TMPRSS 2-ERG基因融合的形成时，受到的代理，导致DNA双链断裂。这些结果提供了一个概念框架的基因融合在人类前列腺癌的起源。在具体目标1中，我们建议采用下一代测序来鉴定由雄激素信号传导介导的全基因组染色体相互作用。导师在生产技术方面的专业知识将帮助候选人获得必要的技能，以实现目标1。有趣的是，我们在雄激素受体AR协作因子FOXA 1中发现了新的复发性突变，该因子在147例前列腺癌中有5例（3.4%）发生突变。对一个代表性突变的初步功能研究显示，突变的FOXA 1破坏雄激素信号传导并增加增殖。在具体目标2中，我们建议研究FOXA 1突变在调节AR信号传导和相互作用组中的作用。目标2是目标1的逻辑延伸，将在独立阶段（R 00）进行。这两个目标的实现将使我们全面了解前列腺细胞的三维基因组结构，AR如何调节这种结构，AR协作因子中的影响突变，以及重要的是如何影响基因融合的形成。虽然空间接近对于染色体易位是必要的，但这是不够的。DNA断裂与空间邻近协同作用以促进染色体易位。在具体目标3中，我们将研究炎症介导的NF-κ B通路活化在前列腺癌中DNA断裂和ETS基因融合形成中的作用。成功完成本提案中概述的目标将提高我们对前列腺癌染色体易位起源的理解，可能对理解和治疗癌症具有更广泛的意义，并可能为人类前列腺癌的一般病因学提供建议。这些项目是根据我的原始想法构思的。Chinnaiyan博士对我的职业目标给予了全力支持，并鼓励我将来将这些项目带到我的独立实验室。