Molecular pathways linking obesity and RCC tumorigenesis (PQ1)

描述(由申请人提供)：本申请是针对RFA-CA-11-011“对NCI挑衅性问题的研究解答(R01)”而提交的，并特别侧重于回答PQ-1：“肥胖如何导致癌症风险？”这一应用建立在大量生物标本收集的基础上，包括胚系DNA、正常组织和肿瘤组织，以及德克萨斯州正在进行的一项肾细胞癌(RCC)病例对照研究的全面流行病学数据，包括饮食、肥胖和体力活动。目前，我们从MD Anderson癌症中心收集了1270名新诊断的德克萨斯州RCC患者和1200名匹配的对照，这些患者来自德克萨斯州居民的随机数字拨号。到拨款到位时，我们估计将招募至少50名病例和50名对照人员。我们计划再招募350名患者和350名对照组。该应用程序将调查肥胖和能量平衡在调节肾细胞癌风险中的作用，以此作为明确理解共同导致肥胖和癌症发展的因素的一步。我们将测试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)推动肾癌发生的假设，这些因素与肥胖和能量平衡(饮食摄入量和体力活动)之间的相互作用可以进一步调节风险。为此，我们将探索四个具体目标：1)寻找新的肾癌风险的胚系易感基因，重点关注肥胖相关基因座和甲基化和miRNA途径的变异。我们将使用两阶段设计首先筛选约10,000个以前发现的与肥胖相关的基因座和潜在的功能 2)确定mtDNA改变(拷贝数和遗传变异)对肾癌风险的影响，并评估mtDNA改变、肥胖、饮食、体力活动和im1中发现的遗传变异在调节肾癌风险中的联合作用。我们将在1,600名患者和1,600名对照中检测所有144个微小等位基因频率的线粒体SNPs的拷贝数和分型；3)确定肥胖相关基因和miRNA在400对配对肾癌和邻近正常组织中的CpG岛甲基化状态，以及在1,600例和1,600名对照和400对配对的肾癌和邻近正常组织中的全局甲基化状态；我们将确定肥胖和能量平衡对这些表型的相互作用；4)评估肥胖相关途径中的基因-表型相关性以及mtDNA含量和表观遗传事件。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概况，这一综合项目不仅将为肾癌的病因和发病机制提供重要的线索，还将确定这些分子途径在肥胖和癌症发展中的共性。

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.