Markers of Susceptibility as Predictors of Blasser Cancer Recurrence

易感标志物可作为膀胱癌复发的预测指标 我们计划在流行病学和遗传学发现以及现有的标本和数据库的基础上，从 最初的孢子项目和我们资助的研究，以评估膀胱癌(BC)复发的预测因素 浅表性BC患者。我们之前已经在烟草途径中发现了几个有希望的标记。 致癌物激活/解毒和DNA损伤/修复。现在我们提议扩展我们的候选基因 一种基于通路的系统研究遗传多态联合影响的方法的探讨 关于临床结果的具体途径；将我们的小组从代谢和DMA损伤/修复途径扩展到 炎症、氧化应激和TRAIL诱导的细胞凋亡途径；结合临床和流行病学 将数据与遗传数据相结合，建立BC复发的定量风险评估模型；将我们的研究与 一项正在进行的针对浅表性BC的卡介苗临床试验；最后，探索SNPs的功能意义。我们的 具体目标如下：(1)。1A.建立一个具有良好特征的800例浅表性BC患者的队列； 评估所有800例患者的遗传易感标记频率，包括相关基因中的SNPs 在炎症过程中，氧化应激和TRAIL诱导细胞凋亡。我们的假设是 这些基因的多态与BC复发的风险相关，也可能对 卡介苗对浅表性BC患者的治疗反应。1C。建立BC的风险评估模型 复发。我们将把临床和流行病学数据与上述研究的基因数据结合起来 以上以及从最初的赠款中建立了BC复发的定量风险评估模型。遗传 代谢酶基因、微环境基因和DNA修复基因的变异将从我们的 其他资金来源将纳入该模式。(2)。评估卡介苗治疗反应的决定因素 200例浅表性BC患者参加临床试验。我们将检测IL-2、IL-8和TRAIL的蛋白水平 在排空的尿液样本中。我们将把这些蛋白质水平与SNPs相关的途径联系起来 卡介苗的作用(特别是参与炎症、氧化应激和TRAIL凋亡途径的基因 复发率。我们的假设是，基因中的特定基因类型与卡介苗的作用机制有关 行动可能会对BC患者对该疗法的治疗反应产生负面影响。作为次要角色 目的，我们将使用实验方法和/或计算方法来验证或发现功能 前景看好的多态的影响。我们的假设是SNPs与膀胱癌复发有关 改变他们基因的功能。能够快速筛查个人的BC复发风险使用最低限度 侵入性程序(血液和尿液样本)具有巨大的临床价值。这些标记将用于 确定复发风险较高的患者亚群，他们应该接受更密集的筛查。标记： 治疗反应可用于制定个体化治疗方案。

MARKERS OF SUSCEPTIBILITY AS PREDICTORS OF BLADDER CANCER RECURRENCE We plan to build upon the epidemiologic and genetic findings and the existing specimen and data repository from the initial SPORE project and our funded research to evaluate predictors of bladder cancer (BC) recurrence in 800 patients with superficial BC. We have previously identified several promising markers in pathways for tobacco carcinogen activation/detoxification and DMA damage/repair. Now we propose to extend our candidate gene approach to a pathway-based approach to systematically examine the joint influence of genetic polymorphisms in specific pathways on clinical outcome; to extend our panel from metabolism and DMA damage/repair pathways to inflammation, oxidative stress, and the TRAIL-induced apoptosis pathways; to integrate clinical and epidemiologic data with the genetic data to build a quantitative risk assessment model for BC recurrence; to link our research to an ongoing BCG clinical trial on superficial BC; and finally to explore functional significance of the SNPs. Our specific aims are as follows: (1). 1a. Construct a well-characterized cohort of 800 patients with superficial BC; 1b. Assess frequencies of genetic predisposition markers in all 800 cases including SNPs in genes that are involved in inflammatory processes, oxidative stress, and TRAIL induced apoptosis. Our hypothesis is that polymorphisms in these genes are associated with risk of BC recurrence, and may also have effects on BCG treatment response in patients with superficial BC. 1c. Build up risk assessment model for BC recurrence. We will integrate clinical and epidemiologic data with the genetic data from the studies described above as well as from the initial grants to build a quantitative risk assessment model for BC recurrence. Genetic variations on metabolic enzyme genes, microenvironment genes, and DNA repair genes will be available from our other funding sources to be incorporated into the model. (2). Assess determinants of BCG treatment response in 200 patients with superficial BC enrolled in a clinical trial. We will measure protein levels of IL-2, IL-8, and TRAIL in voided urine specimens. We will correlate these protein levels as well as SNPs in pathways relevant to the the action of BCG (especially genes involved in inflammation, oxidative stress, and TRAIL apoptosis pathways with recurrence rates. Our hypothesis is that specific genotypes in genes related to the mechanism of BCG action may negatively affect the treatment response of patients with BC to this therapy. As a secondary aim, we will use experimental approaches and/or computational approaches to verify or discover the functional impact of promising polymorphisms. Our hypothesis is that SNPs associated with bladder cancer recurrence alter the function of their genes. The ability to rapidly screen individuals for BC recurrence risk using minimally invasive procedures (blood and urine samples) has immense clinical value. These markers will be useful for identifying patient subgroups at high risk for recurrence who should undergo more intensive screening. Markers of treatment response could be used to design individualized treatment plans.