Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

项目摘要和摘要 这项提议的总体目标是支持拜伦·李博士成为一名独立调查人员的培训 进行膀胱癌表观基因组学的翻译研究。李博士将由尼玛·沙里菲博士指导 以及彼得·斯卡切里博士。尼玛·沙里菲博士是该案泌尿生殖系统恶性肿瘤项目的负责人 综合癌症中心，并指导了许多年轻的内科科学家。彼得·斯卡切里博士是 凯斯西储大学遗传学教授，癌症表观基因组学专家。培训 PLAN包含以下目标：(1)加强对染色质生物学的了解，(2)获得 生物信息学分析复杂的生物数据，以及(3)熟练使用患者派生的 翻译研究的样本。膀胱癌是世界上第五大最常见的非皮肤恶性肿瘤。 美国，但几乎没有新的治疗选择。癌症基因组图谱(TCGA)，一项大规模的努力 在NCI和NHGRI的支持下，确定癌症的分子基础，进行了综合分子 400多例肌肉浸润性膀胱癌的特征及染色质修饰基因 75%的病例会发生改变。这些改变中的大多数被预测会导致功能丧失；然而， 它们对膀胱癌的发生、发展和治疗反应的影响在很大程度上是未知的。这些基因 改变DNA-组蛋白界面的配置，从而影响DNA结合蛋白的访问能力 它们的目标序列。将被检验的中心假设是染色质修饰基因突变导致 通过增强子干扰支持膀胱癌启动和进展的基因表达变化。 为了实现这一目标，我们提出了以下具体目标：(1)检验KDM6A失活的假设 改变尿路上皮细胞的染色质状态并产生导致肿瘤的转录程序 生长，以及(2)检验增强子功能障碍和异常转录电路表征的假设 人类膀胱癌和对这些回路的依赖导致对现有靶向的易感性 治疗。成功完成拟议的研究将促进我们对染色质如何 修饰基因突变是膀胱癌最常见的体细胞改变之一，影响疾病的发生 和进步。此外，我们希望确定由增强子干扰和 转录因子回路的变化。针对这些漏洞可以导致开发新的 膀胱癌的治疗方法。

Project Summary and Abstract The overall goal of this proposal is to support the training of Dr. Byron Lee to become an independent investigator conducting translational research in bladder cancer epigenomics. Dr. Lee will be mentored by Dr. Nima Sharifi and Dr. Peter Scacheri. Dr. Nima Sharifi is the leader of the Genitourinary Malignancies Program at the Case Comprehensive Cancer Center and has mentored numerous young physician-scientists. Dr. Peter Scacheri is Professor of Genetics at Case Western Reserve University and an expert in cancer epigenomics. The training plan incorporates the following goals: (1) enhance understanding of chromatin biology, (2) gain expertise in bioinformatics analysis of complex biological data, and (3) develop proficiency in the use of patient-derived samples for translational research. Bladder cancer is the fifth most common non-cutaneous malignancy in the United States, yet few new treatment options exist. The Cancer Genome Atlas (TCGA), a large-scale effort supported by NCI and NHGRI to determine the molecular basis of cancer, performed comprehensive molecular characterization of over 400 muscle invasive bladder cancers and showed that chromatin modifier gene alterations occur in 75% of cases. Most of these alterations are predicted to result in loss of function; however, their effects on bladder cancer initiation, progression, and response to therapy are largely unknown. These genes alter the configuration of the DNA-histone interface, which affects the ability of DNA-binding proteins to access their target sequences. The central hypothesis that will be tested is that chromatin modifier gene mutation leads to gene expression changes that support bladder cancer initiation and progression through enhancer disruption. To accomplish this goal, we propose the following Specific Aims: (1) Test the hypothesis that KDM6A inactivation alters the chromatin state of urothelial cells and engenders a transcriptional program that results in neoplastic growth, and (2) Test the hypothesis that enhancer dysfunction and aberrant transcriptional circuits characterize human bladder cancer and dependence on these circuits for growth result in vulnerability to existing targeted therapies. Successful completion of the proposed research will advance our understanding of how chromatin modifier gene mutations, one of the most frequent somatic alterations in bladder cancer, affect disease initiation and progression. Moreover, we expect to identify molecular vulnerabilities arising from enhancer disruption and changes in transcription factor circuits. Targeting these vulnerabilities can lead to the development of novel therapies for bladder cancer.