Molecular pathways linking obesity and RCC tumorigenesis (PQ1)

连接肥胖和肾细胞癌肿瘤发生的分子途径 (PQ1)

基本信息

批准号：
8538909
负责人：
Xifeng Wu
金额：
$ 50.53万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538909
关键词：
Address Age Anabolism Binding Proteins Biological Biology Cancer Center Case-Control Studies Cells Collection CpG Islands DNA DNA Methylation DNA copy number Data Databases Development Diet Dietary intake Digit structure Energy-Generating Resources Enzymes Epidemiology Epigenetic Process Ethnic Origin Etiology Event Frequencies Funding Gender Gene Frequency Gene Mutation Generations Genes Genetic Genetic Polymorphism Genetic Variation Genotype Grant Haplotypes Heritability Homeostasis Incidence Individual Joints Light Link Malignant Neoplasms Measures Methylation MicroRNAs Minor Mitochondria Mitochondrial DNA Molecular Molecular Profiling NIH Program Announcements Newly Diagnosed Normal tissue morphology Obesity Pathogenesis Pathway interactions Patients Pattern Phenotype Physical activity Pilot Projects Ploidies Predisposition Recruitment Activity Renal Cell Carcinoma Reporting Research Research Design Research Project Grants Risk Risk Factors Role Site Staging Testing Texas Time Tumor Tissue Variant base cancer risk design energy balance genome wide association study innovation insight novel residence response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): This application is submitted in response RFA-CA-11-011 "Research Answers to NCI's Provocative Questions (R01)" and specifically focuses on addressing PQ-1: "How does obesity contribute to cancer risk?" This application builds upon the large collection of biospecimens including germline DNA, normal and tumor tissues, and comprehensive epidemiology data including diet, obesity, and physical activity of an ongoing renal cell carcinoma (RCC) case control study from Texas. Currently, we have accrued 1,270 patients with newly diagnosed RCC of Texas residence from MD Anderson Cancer Center and 1,200 matched controls identified from random digit dialing of Texas residents. By the time the grant is funded, we estimate to recruit at least 50 cases and 50 controls. We plan to recruit an additional 350 patients and 350 controls. The application will investigate the role of obesity and energy balance in modulating RCC risk as a step towards a clear understanding of the factors that contribute jointly to obesity and cancer development. We will test the hypothesis that obesity-related genetic variations, mtDNA alterations, and epigenetic status (microRNA and methylation) drive RCC tumorigenesis, and interactions among these factors with obesity and energy balance (dietary intake and physical activity) can further modulate risk. Towards this, we will explore 4 specific aims: 1) To identify novel germline susceptibility loci for RCC risk focusig on obesity-related loci and variation in methylation and miRNA pathways. We will use two-stage design to first screen ~ 10,000 previously identified obesity-related loci and potential functional and haplotype-tagging SNPs in epigenetic pathway genes in 800 cases and 800 controls and then validate top 500 SNPs in additional 800 cases and 800 controls; 2) To determine the effect of mtDNA alterations (copy number and genetic variations) on RCC risk and evaluate the joint effect of mtDNA alterations, obesity, diet, physical activity, and genetic variation identified in im 1 in modulating RCC risk. We will measure mtDNA copy number and genotype all the 144 mitochondrial SNPs with a minor allele frequency >1% in 1,600 cases and 1,600 controls; 3) To identify CpG island methylation of obesity-related genes and miRNA expression patterns in 400 paired RCC tumors and adjacent normal tissues and global methylation status in 1,600 cases and 1,600 controls and 400 paired RCC tumors and adjacent normal tissues; We will determine the interplay between of obesity and energy balance on these phenotypes; 4) To assess genotype-phenotype correlations in obesity-related pathways and mtDNA content and epigenetic events. By integrating epidemiological data, germline genetic variations associated with obesity and epigenetic alterations, mitochondrial function, and profiling of epigenetic alterations in tumors, this comprehensive project will not only shed significant light into the etiology and pathogenesis of RCC, but also identify the commonality of these molecular pathways in obesity and cancer development.

描述（由申请人提供）：此申请是在REPHONS RFA-CA-11-11中提交的“ NCI挑衅性问题的研究答案（R01）”，特别专注于解决PQ-1：“肥胖对癌症风险有何贡献？”该应用建立在大量生物测量基础上，包括种系DNA，正常和肿瘤组织，以及全面的流行病学数据，包括饮食，肥胖和正在进行的肾脏细胞癌（RCC）病例对照研究的身体活动。目前，我们从MD安德森癌症中心（MD Anderson Cencer Center）获得了1,270例新诊断为德克萨斯州RCC的患者，并从德克萨斯州居民随机数字拨号中确定的1,200个匹配的对照组。到资助赠款时，我们估计将招募至少50个案件和50个对照。我们计划招募另外350名患者和350例对照。该应用将调查肥胖和能量平衡在调节RCC风险中的作用，以了解对共同促进肥胖和癌症发展的因素的明确了解。我们将检验以下假设：与肥胖相关的遗传变异，mtDNA改变以及表观遗传状态（microRNA和甲基化）驱动RCC肿瘤发生，以及这些因肥胖和能量平衡（饮食摄入和体育活动）的相互作用可以进一步调节风险。在此方面，我们将探讨4个特定目标：1）确定新型种系易感性基因座，以将RCC风险重点放在与肥胖相关的基因座以及甲基化和miRNA途径的变化上。我们将使用两个阶段的设计进行第一个屏幕〜10,000先前确定的与肥胖相关的基因座和潜在功能在800例和800个对照中，表观遗传途径基因中的单倍型标记SNP，然后在另外800例和800个对照中验证前500个SNP； 2）确定mtDNA改变（拷贝数和遗传变异）对RCC风险的影响，并评估IM 1中MTDNA改变，肥胖，饮食，饮食，体育活动和遗传变异的关节作用在调节RCC风险中。我们将测量MTDNA拷贝数和基因型，所有144个线粒体SNP的次要等位基因频率在1,600例和1,600个对照中> 1％； 3）在1,600例和1,600例对照组中，在400个配对的RCC肿瘤和邻近的正常组织中鉴定与肥胖相关基因和miRNA表达模式的CpG岛甲基化以及400个配对的RCC肿瘤和相邻正常组织中的CpG岛甲基化；我们将确定这些表型上肥胖与能量平衡之间的相互作用。 4）评估与肥胖相关途径和mtDNA含量和表观遗传事件的基因型 - 表型相关性。通过整合流行病学数据，与肥胖和表观遗传学改变，线粒体功能以及肿瘤表观遗传学改变的谱分析相关的种系遗传变异，这一综合性项目不仅会向RCC的病因学和发病机理带来重大影响，而且还确定了这些综合性肥胖和癌症发展中的分子途径。