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)

• 批准号: 8686604
• 负责人: Xifeng Wu
• 金额: $ 52.12万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/8686604
• 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

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）：本申请是为了响应 RFA-CA-11-011“NCI 的挑衅性问题 (R01) 的研究答案”而提交，特别侧重于解决 PQ-1：“肥胖如何导致癌症风险？”该应用程序建立在德克萨斯州正在进行的肾细胞癌 (RCC) 病例对照研究的大量生物样本（包括种系 DNA、正常组织和肿瘤组织）以及全面的流行病学数据（包括饮食、肥胖和体力活动）的基础上。目前，我们已从 MD 安德森癌症中心收集了 1,270 名新诊断的德克萨斯州居民的 RCC 患者，并从德克萨斯州居民的随机数字拨号中识别出 1,200 名匹配的对照者。到拨款到位时，我们预计将招募至少 50 个病例和 50 个对照。我们计划另外招募 350 名患者和 350 名对照者。该应用程序将研究肥胖和能量平衡在调节肾细胞癌风险中的作用，作为清楚了解共同导致肥胖和癌症发展的因素的一步。我们将检验以下假设：与肥胖相关的遗传变异、mtDNA 改变和表观遗传状态（microRNA 和甲基化）驱动 RCC 肿瘤发生，并且这些因素与肥胖和能量平衡（饮食摄入和体力活动）之间的相互作用可以进一步调节风险。为此，我们将探索 4 个具体目标：1）确定 RCC 风险的新种系易感位点，重点关注肥胖相关位点以及甲基化和 miRNA 途径的变化。我们将使用两阶段设计来首次筛选约 10,000 个先前确定的肥胖相关基因座和潜在的功能基因座 在 800 个病例和 800 个对照的表观遗传途径基因中进行单倍型标记 SNP，然后在另外 800 个病例和 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 mtDNA 改变、肥胖、饮食、体力活动和 im 1 中确定的遗传变异在调节 RCC 风险中的联合效应。我们将测量 1,600 个病例和 1,600 个对照中所有 144 个线粒体 SNP（次要等位基因频率 >1%）的 mtDNA 拷贝数和基因型； 3）确定400个配对的RCC肿瘤和邻近正常组织中肥胖相关基因的CpG岛甲基化和miRNA表达模式，以及1,600个病例和1,600个对照以及400个配对的RCC肿瘤和邻近正常组织中的整体甲基化状态；我们将确定肥胖和能量平衡对这些表型的相互作用； 4) 评估肥胖相关途径、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、与肥胖和表观遗传改变相关的种系遗传变异、线粒体功能以及肿瘤表观遗传改变的分析，这个综合项目不仅将揭示肾细胞癌的病因和发病机制，而且还将确定这些分子途径在肥胖和癌症发展中的共性。