Grant Number:	5R01CA170298-04 Interpret this number
Primary Investigator:	Gu, Jian
Organization:	University Of Tx Md Anderson Can Ctr
Project Title:	Molecular Pathways Linking Obesity and Rcc Tumorigenesis (PQ1)
Fiscal Year:	2015

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.




Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients.
Authors: Wang Q. , Zhang J. , Tu H. , Liang D. , Chang D.W. , Ye Y. , Wu X. .
Source: Journal For Immunotherapy Of Cancer, 2019-11-29 00:00:00.0; 7(1), p. 334.
EPub date: 2019-11-29 00:00:00.0.
PMID: 31783776
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Circulating obesity-driven biomarkers are associated with risk of clear cell renal cell carcinoma: a two-stage, case-control study.
Authors: Wang Q. , Tu H. , Zhu M. , Liang D. , Ye Y. , Chang D.W. , Long Y. , Wu X. .
Source: Carcinogenesis, 2019-10-16 00:00:00.0; 40(10), p. 1191-1197.
PMID: 31001636
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Sex specific associations in genome wide association analysis of renal cell carcinoma.
Authors: Laskar R.S. , Muller D.C. , Li P. , Machiela M.J. , Ye Y. , Gaborieau V. , Foll M. , Hofmann J.N. , Colli L. , Sampson J.N. , et al. .
Source: European Journal Of Human Genetics : Ejhg, 2019-06-23 00:00:00.0; , .
EPub date: 2019-06-23 00:00:00.0.
PMID: 31231134
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The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.
Authors: Johansson M. , Carreras-Torres R. , Scelo G. , Purdue M.P. , Mariosa D. , Muller D.C. , Timpson N.J. , Haycock P.C. , Brown K.M. , Wang Z. , et al. .
Source: Plos Medicine, 2019 01; 16(1), p. e1002724.
EPub date: 2019-01-03 00:00:00.0.
PMID: 30605491
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Global and Targeted miRNA Expression Profiling in Clear Cell Renal Cell Carcinoma Tissues Potentially Links miR-155-5p and miR-210-3p to both Tumorigenesis and Recurrence.
Authors: Zhang J. , Ye Y. , Chang D.W. , Lin S.H. , Huang M. , Tannir N.M. , Matin S. , Karam J.A. , Wood C.G. , Chen Z.N. , et al. .
Source: The American Journal Of Pathology, 2018 Nov; 188(11), p. 2487-2496.
EPub date: 2018-09-08 00:00:00.0.
PMID: 30201497
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Germline genetic variants in somatically significantly mutated genes in tumors are associated with renal cell carcinoma risk and outcome.
Authors: Shu X. , Gu J. , Huang M. , Tannir N.M. , Matin S.F. , Karam J.A. , Wood C.G. , Wu X. , Ye Y. .
Source: Carcinogenesis, 2018-05-28 00:00:00.0; 39(6), p. 752-757.
PMID: 29635281
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Cancer risk associated with chronic diseases and disease markers: prospective cohort study.
Authors: Tu H. , Wen C.P. , Tsai S.P. , Chow W.H. , Wen C. , Ye Y. , Zhao H. , Tsai M.K. , Huang M. , Dinney C.P. , et al. .
Source: Bmj (clinical Research Ed.), 2018-01-31 00:00:00.0; 360, p. k134.
EPub date: 2018-01-31 00:00:00.0.
PMID: 29386192
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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
Authors: Machiela M.J. , Hofmann J.N. , Carreras-Torres R. , Brown K.M. , Johansson M. , Wang Z. , Foll M. , Li P. , Rothman N. , Savage S.A. , et al. .
Source: European Urology, 2017 Nov; 72(5), p. 747-754.
EPub date: 2017-08-07 00:00:00.0.
PMID: 28797570
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Glycemic index, glycemic load and carbohydrate intake in association with risk of renal cell carcinoma.
Authors: Zhu J. , Tu H. , Matin S.F. , Tannir N.M. , Wood C.G. , Wu X. .
Source: Carcinogenesis, 2017-10-26 00:00:00.0; 38(11), p. 1129-1135.
PMID: 28968893
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Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer.
Authors: Lin M. , Zhang L. , Hildebrandt M.A.T. , Huang M. , Wu X. , Ye Y. .
Source: Oncotarget, 2017-09-26 00:00:00.0; 8(43), p. 74936-74946.
EPub date: 2017-08-24 00:00:00.0.
PMID: 29088836
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Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes.
Authors: Shu X. , Purdue M.P. , Ye Y. , Tu H. , Wood C.G. , Tannir N.M. , Wang Z. , Albanes D. , Gapstur S.M. , Stevens V.L. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017-06-16 00:00:00.0; , .
EPub date: 2017-06-16 00:00:00.0.
PMID: 28626070
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Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma.
Authors: Mendoza-Pérez J. , Gu J. , Herrera L.A. , Tannir N.M. , Zhang S. , Matin S. , Karam J.A. , Wood C.G. , Wu X. .
Source: Cancer, 2017-05-23 00:00:00.0; , .
EPub date: 2017-05-23 00:00:00.0.
PMID: 28543182
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Microrna Profiling In Clear Cell Renal Cell Carcinoma Tissues Potentially Links Tumorigenesis And Recurrence With Obesity
Authors: Shu X. , Hildebrandt M.A. , Gu J. , Tannir N.M. , Matin S.F. , Karam J.A. , Wood C.G. , Wu X. .
Source: British Journal Of Cancer, 2017-01-03 00:00:00.0; 116(1), p. 77-84.
PMID: 27907930
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Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case-Control Study.
Authors: Mendoza-Pérez J. , Gu J. , Herrera L.A. , Tannir N.M. , Matin S.F. , Karam J.A. , Huang M. , Chang D.W. , Wood C.G. , Wu X. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2016-04-15 00:00:00.0; 22(8), p. 2074-82.
EPub date: 2016-04-15 00:00:00.0.
PMID: 26655847
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Gene-environment interaction of genome-wide association study-identified susceptibility loci and meat-cooking mutagens in the etiology of renal cell carcinoma.
Authors: Melkonian S.C. , Daniel C.R. , Ye Y. , Tannir N.M. , Karam J.A. , Matin S.F. , Wood C.G. , Wu X. .
Source: Cancer, 2016-01-01 00:00:00.0; 122(1), p. 108-15.
EPub date: 2016-01-01 00:00:00.0.
PMID: 26551148
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Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma.
Authors: Shu X. , Purdue M.P. , Ye Y. , Wood C.G. , Chen M. , Wang Z. , Albanes D. , Pu X. , Huang M. , Stevens V.L. , et al. .
Source: Oncotarget, 2015-02-28 00:00:00.0; 6(6), p. 4097-109.
PMID: 25784652
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Mitochondrial DNA copy number in peripheral blood leukocytes and the risk of clear cell renal cell carcinoma.
Authors: Melkonian S.C. , Wang X. , Gu J. , Matin S.F. , Tannir N.M. , Wood C.G. , Wu X. .
Source: Carcinogenesis, 2015 Feb; 36(2), p. 249-55.
PMID: 25524925
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Joint association of genome-wide association study-identified susceptibility loci and dietary patterns in risk of renal cell carcinoma among non-Hispanic whites.
Authors: Melkonian S.C. , Daniel C.R. , Hildebrandt M.A. , Tannir N.M. , Ye Y. , Chow W.H. , Wood C.G. , Wu X. .
Source: American Journal Of Epidemiology, 2014-09-01 00:00:00.0; 180(5), p. 499-507.
EPub date: 2014-09-01 00:00:00.0.
PMID: 25053674
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A genome-wide association study of renal cell carcinoma among African Americans.
Authors: Purdue M.P. , Ye Y. , Wang Z. , Colt J.S. , Schwartz K.L. , Davis F.G. , Rothman N. , Chow W.H. , Wu X. , Chanock S.J. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Jan; 23(1), p. 209-14.
PMID: 24220910
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Energy balance, polymorphisms in the mTOR pathway, and renal cell carcinoma risk.
Authors: Shu X. , Lin J. , Wood C.G. , Tannir N.M. , Wu X. .
Source: Journal Of The National Cancer Institute, 2013-03-20 00:00:00.0; 105(6), p. 424-32.
EPub date: 2013-03-20 00:00:00.0.
PMID: 23378641
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Deficiency of cell cycle checkpoints and DNA repair system predispose individuals to esophageal cancer.
Authors: Shao L. , Hittelman W.N. , Lin J. , Yang H. , Ajani J.A. , Wu X. .
Source: Mutation Research, 2006-12-01 00:00:00.0; 602(1-2), p. 143-50.
EPub date: 2006-12-01 00:00:00.0.
PMID: 17011594
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