DE NOVO DNA METHYLATION IN BLADDER CANCER

描述（由申请人提供）：膀胱癌在美国很常见，相对于其对公共卫生的影响，膀胱癌的研究相对不足。本项目旨在了解胞嘧啶残基异常甲基化引起的凋亡基因的表观遗传沉默是如何作为年龄和致癌作用的函数发生的。我们已经发现，我们可以使用定量MethyLight高通量平台来检测尿沉积物中的DNA甲基化变化，这为我们提供了使用非侵入性采样技术以纵向方式研究癌症演变和进展的独特机会。我们希望利用尿沉淀物的可用性，将我们的基础科学发现转化为有助于识别复发性肿瘤的策略。由于复发是浅表性膀胱癌的常见特征，因此这些目标的实现将对患者的生活质量产生深远的影响。为了实现这些目标，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位点上游和下游的CpG岛标记物组的开发，并验证在尿沉渣中观察到的甲基化与原发性肿瘤中的甲基化相对应。其次，我们将利用尿沉渣系统来确定DNA甲基化模式如何在膀胱中随着年龄的增长而演变。第三，我们将对因浅表性或浸润性膀胱癌接受手术治疗的患者进行连续研究，以确定在通过常规方法检测到复发肿瘤之前，初次手术切除时存在的甲基化模式是否重新出现在尿沉积物中。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，而且还可以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.