Molecular pathways linking obesity and RCC tumorigenesis (PQ1)

描述（由申请人提供）：本申请是为了响应RFA-CA-11 - 011 "NCI挑衅性问题的研究答案（R01）"而提交的，特别关注解决PQ-1："肥胖如何导致癌症风险？“该应用程序建立在大量生物标本的基础上，包括生殖系DNA，正常和肿瘤组织，以及全面的流行病学数据，包括饮食，肥胖和德克萨斯州正在进行的肾细胞癌（RCC）病例对照研究的身体活动。目前，我们已经从MD安德森癌症中心收集了1,270例新诊断的德克萨斯州RCC患者，并从德克萨斯州居民的随机数字拨号中确定了1,200例匹配的对照。到补助金到位时，我们估计至少招募50例病例和50例对照。我们计划再招募350名患者和350名对照。该应用程序将研究肥胖和能量平衡在调节RCC风险中的作用，作为明确了解肥胖和癌症发展共同因素的一步。我们将检验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肿瘤发生的假设，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）确定新的生殖系易感基因座RCC风险集中在肥胖相关基因座和甲基化和miRNA途径的变异。我们将采用两阶段设计，首先筛选约10，000个先前确定的肥胖相关基因座和潜在的功能基因座。 对800例病例和800例对照的表观遗传通路基因进行单倍型标记SNPs，并对另外800例病例和800例对照的前500个SNPs进行验证; 2）确定mtDNA改变的影响（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、在调节RCC风险中，在im 1中鉴定出遗传变异。我们将在1,600例病例和1,600例对照中测量所有144个次要等位基因频率> 1%的线粒体SNP的mtDNA拷贝数和基因型; 3）检测400对RCC肿瘤及癌旁正常组织中肥胖相关基因CpG岛甲基化和miRNA表达模式，以及1,600例病例和1例对照组的总体甲基化状态，600例对照和400例配对的RCC肿瘤和邻近正常组织;我们将确定肥胖和能量平衡对这些表型的相互作用; 4）评估肥胖相关通路和mtDNA含量以及表观遗传事件中的基因型-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为RCC的病因和发病机制提供重要的启示，而且还将确定这些分子途径在肥胖和癌症发展中的共同性。

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.