Markers of Susceptibility as Predictors of Blasser Cancer Recurrence

易感性标记物作为 Blasser 癌症复发的预测因子

• 批准号: 7729505
• 负责人: Xifeng Wu
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729505
• 关键词: APEX1 gene; Accounting; Affect; Apoptosis; Apoptotic; Base Excision Repairs; Bioinformatics; Biological; Blood; Body Weight decreased; Body mass index; COMT gene; Calmette-Guerin Bacillus; Candidate Disease Gene; Catechol O-Methyltransferase; Clinical; Clinical Trials; Cytokine Receptors; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Databases; Demographic Factors; Development; Diagnosis; Dietary intake; Drug Metabolic Detoxication; Enrollment; Enzyme Gene; Enzyme-Linked Immunosorbent Assay; Evolution; Family Cancer History; Free Radicals; Frequencies; Funding; Funding Agency; GSTM1 gene; GSTP1 gene; GSTT1 gene; GSTT1 protein; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Grant; IL8 gene; Individual; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-1 alpha; Interleukin-10; Interleukin-12; Interleukin-18; Interleukin-4; Interleukin-5; Interleukin-6; Invasive; Joints; Link; Malignant neoplasm of urinary bladder; Measures; Metabolic; Metabolism; Micronutrients; Modeling; Molecular; Molecular Biology; Molecular Epidemiology; Molecular Genetics; Molecular and Cellular Biology; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Newly Diagnosed; Outcome; Oxidative Stress; PTGS2 gene; Pathway interactions; Patients; Pattern; Performance Status; Phenotype; Predisposition; Primary Neoplasm; Procedures; Process; Production; Program Description; Proteins; Rate; Recruitment Activity; Recurrence; Reproducibility; Reproduction spores; Research; Research Personnel; Risk; Risk Assessment; Sampling; Screening procedure; Single Nucleotide Polymorphism; Smoking Status; Specimen; Subgroup; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Time; Tobacco-Associated Carcinogen; Translational Research; Urination; Urine; XRCC1 gene; base; cancer recurrence; caspase-8; cigarette smoking; cohort; design; follow-up; glutathione S-transferase M1; glutathione S-transferase pi; multidisciplinary; outcome forecast; repaired; response; treatment planning; tumor

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.

膀胱癌复发的易感性指标预测 我们计划在流行病学和遗传学发现以及现有标本和数据库的基础上， 最初的SPORE项目和我们资助的研究，以评估800例膀胱癌（BC）复发的预测因素， 浅表性BC患者。我们以前已经确定了几个有希望的标记在烟草的途径 致癌物活化/解毒和DMA损伤/修复。现在我们建议将候选基因 方法的途径为基础的方法，系统地检查遗传多态性的联合影响， 临床结果的特定途径;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诱导的凋亡途径;整合临床和流行病学 数据与基因数据，以建立一个定量的风险评估模型，为BC复发;将我们的研究， 正在进行的卡介苗对浅表性BC的临床试验;最后探讨SNP的功能意义。我们 具体目标如下：（1）. 1a.构建一个由800名浅表性BC患者组成的特征明确的队列; 1b. 评估所有800例病例中遗传易感性标志物的频率，包括相关基因中的SNP 炎症过程、氧化应激和TRAIL诱导的细胞凋亡。我们的假设是 这些基因中的多态性与BC复发的风险相关，并且还可能对 浅表性BC患者的BCG治疗反应。1c.建立BC风险评估模型 复发我们将整合临床和流行病学数据与遗传数据的研究所描述的 上述以及从最初的赠款，建立一个量化的风险评估模型，BC复发。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 其他供资来源将纳入该模式。（二）、评估BCG治疗反应的决定因素， 200例浅表BC患者入组临床试验。我们将测量IL-2、IL-8和TRAIL的蛋白水平， 尿液样本中发现的我们将把这些蛋白质水平以及与这些蛋白质水平相关的通路中的SNPs关联起来。 BCG的作用（尤其是参与炎症、氧化应激和TRAIL凋亡途径的基因， 复发率我们的假设是与BCG作用机制相关的基因中的特定基因型 这可能会对BC患者对该疗法的治疗反应产生负面影响。作为次要 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 有希望的多态性的影响。我们假设与膀胱癌复发相关的SNPs 改变他们基因的功能。使用最低限度的放射性核素快速筛查个体BC复发风险的能力 侵入性程序（血液和尿液样本）具有巨大的临床价值。这些标记将有助于 确定复发风险高的患者亚组，这些患者应接受更密集的筛查。标志物 治疗反应可用于设计个体化治疗计划。