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.

Public Health Relevance

The incidence of renal cell carcinoma (RCC) has been steadily increasing in the past 2 decades at 2% per year and obesity is a major risk factor for RCC. There has been accumulating evidence that obesity and energy imbalance (e.g., dietary intake, and physical activity) leads increased cancer risk;therefore, we designed this study to systemically evaluate the interplay of obesity and obesity-related genetic variation and phenotypes, such as mtDNA alterations and epigenetic patterns (methylation and microRNA expression), in the etiology and pathogenesis of RCC. The results will provide insight regarding the key pathways that link obesity to cancer development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1)
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Agurs-Collins, Tanya
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University of Texas MD Anderson Cancer Center
Public Health & Prev Medicine
Overall Medical
United States
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Lin, Moubin; Zhang, Liren; Hildebrandt, Michelle A T et al. (2017) Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer. Oncotarget 8:74936-74946
Machiela, Mitchell J; Hofmann, Jonathan N; Carreras-Torres, Robert et al. (2017) Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. Eur Urol 72:747-754
Shu, Xiang; Purdue, Mark P; Ye, Yuanqing et al. (2017) Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes. Cancer Epidemiol Biomarkers Prev 26:1436-1442
Shu, X; Hildebrandt, M A; Gu, J et al. (2017) MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity. Br J Cancer 116:77-84
Mendoza-Pérez, Julia; Gu, Jian; Herrera, Luis A et al. (2017) Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma. Cancer 123:3617-3627
Mendoza-Pérez, Julia; Gu, Jian; Herrera, Luis A et al. (2016) Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study. Clin Cancer Res 22:2074-82
Melkonian, Stephanie C; Daniel, Carrie R; Ye, Yuanqing et al. (2016) Gene-environment interaction of genome-wide association study-identified susceptibility loci and meat-cooking mutagens in the etiology of renal cell carcinoma. Cancer 122:108-15
Melkonian, Stephanie C; Wang, Xin; Gu, Jian et al. (2015) Mitochondrial DNA copy number in peripheral blood leukocytes and the risk of clear cell renal cell carcinoma. Carcinogenesis 36:249-55
Shu, Xiang; Purdue, Mark P; Ye, Yuanqing et al. (2015) Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma. Oncotarget 6:4097-109
Purdue, Mark P; Ye, Yuanqing; Wang, Zhaoming et al. (2014) A genome-wide association study of renal cell carcinoma among African Americans. Cancer Epidemiol Biomarkers Prev 23:209-14

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