DE NOVO DNA METHYLATION IN BLADDER CANCER

描述(申请人提供)：膀胱癌在美国很常见，相对于其对公共健康的影响，研究相对较少。这个项目试图了解如何通过胞嘧啶残基的异常甲基化使凋亡基因的表观遗传沉默作为年龄和癌症发生的函数。我们发现，我们可以使用定量的MethyLight高通量平台来检测尿沉渣中DNA甲基化的变化，这为我们提供了使用非侵入性采样技术纵向研究癌症进化和进展的独特机会。我们希望利用尿沉渣的可用性，将我们的基础科学发现转化为有助于识别复发肿瘤的策略。由于复发是浅表性膀胱癌的常见特征，这些目标的实现将对患者的生活质量产生深远的影响。为实现这些目标，我们将实现以下具体目标。首先，我们将完成位于凋亡基因转录起始点上游和下游的CpG岛的标记面板的开发，并验证在尿沉渣中观察到的甲基化与原发肿瘤中的甲基化一致。其次，我们将利用尿沉渣系统来确定DNA甲基化模式是如何随着年龄的增长而在膀胱中演变的。第三，我们会对曾接受浅表性或浸润性膀胱癌手术治疗的患者进行连续研究，以确定首次手术切除时存在的甲基化模式是否会在常规方法检测到肿瘤复发之前在尿沉渣中重新出现。因此，这三个具体目标的实现将使我们不仅能够了解膀胱癌的表观遗传学，而且还将利用这些基本发现来改善这种疾病患者的生活。

DESCRIPTION (provided by applicant): Bladder cancer is common in the United States and is bnmkjrelatively understudied relative to its public health implications. This project seeks to understand how the epigenetic silencing of apoptotic genes by abnormal methylation of cytosine residues occurs as a function of age and carcinogenesis. We have discovered that we can use the quantitative MethyLight high throughput platform to detect DNA methylation changes in urine sediments, which gives us unique opportunities to study cancer evolution and progression in a longitudinal fashion using a noninvasive sampling technique. We wish to take advantage of the availability of urine sediments to translate our basic science discoveries into strategies which can assist in the identification of recurrent tumors. Since recurrence is a common feature of superficial bladder cancer, the achievements of these goals would have profound impact on the patient's quality of life. To achieve these goals we will accomplish the following specific aims. First, we will complete the development of a marker panel of CpG islands located upstream and just downstream of the transcription start sites of apoptotic genes and verify that methylation observed in urine sediments corresponds with methylation in the primary tumors. Secondly, we will take advantage of the urine sediment system to ascertain how DNA methylation patterns evolve in the urinary bladder as a function of aging. Thirdly, we will conduct consecutive studies on patients who have been surgically treated for either superficial or invasive bladder cancer to determine whether the methylation patterns present at the time of initial surgical excision reappear in the urine sediments before the recurrent tumors can be detected by conventional means. Thus, the achievement of these three specific aims will allow us not only to understand the epigenetics of bladder cancer but also use these fundamental discoveries to better the lives of patients with this disease.