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National Institutes of Health: National Cancer Institute: Division of Cancer Control and Population Sciences
Grant Details

Grant Number: 5R01CA136726-05 Interpret this number
Primary Investigator: Li, Li
Organization: Case Western Reserve University
Project Title: Obesity-Related Insulin Resistance Signaling Pathway Factors and Colon Cancer
Fiscal Year: 2013
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Abstract

Project Summary Obesity is now established as a potential cause for colon cancer. While the underlying mechanisms mediating the obesity-colon cancer link are not well understood, increasing evidence supports that Insulin resistance resulting from long-term energy imbalance and subsequent perturbation of metabolic homeostasis and insulin signaling pathways form the core of obesity-related colon carcinogenesis. Genetic variations within genes in key insulin and growth factor signaling pathways may, or in combination with obesity, drive the development of colon cancer, but have been little studied. The fact that obesity is escalating as an epidemic worldwide makes the exploration of the mechanistic connections between obesity and colon cancer a pressing public health and research priority. Therefore, we propose a genetic epidemiologic study of the relation of colon cancer with obesity and candidate genes in four critical insulin and related growth factor signaling pathways: 1) phosphatidylinositol-3 Kinase/protein kinase B (PI3K/AKT) signaling cascade; 2) AMP-activated protein kinase (AMPK) pathway; 3) mitogen-activated protein (MAP) kinase pathway; and 4) peroxisome proliferators-activated receptors (PPARs). Each of these pathways plays an important role linking increased adiposity to colon carcinogenesis and model systems indicate that crosstalk occurs among them. We will use both conventional statistical approaches and a novel hierarchical model to comprehensively evaluate obesity and adult weight gain, candidate gene polymorphisms and haplotypes, and their potential joint and interactive effects on colon cancer. The unifying theme of this proposal is that obesity and candidate gene variants within these pathways may act alone or jointly to drive colon carcinogenesis. This study builds upon an ongoing population-based case-control study where epidemiologic data and DNA samples from 1,250 incident colon cancer cases and 1,500 population controls has already being collected. This relatively large study population will be readily available and allow us to dissect complex gene-gene and gene-obesity interactions to gain in- depth understanding of mechanistic link between obesity and colon carcinogenesis.

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Publications

Associations Between Obesity And Changes In Adult Bmi Over Time And Colon Cancer Risk
Authors: Nock N.L. , Thompson C.L. , Tucker T.C. , Berger N.A. , Li L. .
Source: Obesity (silver Spring, Md.), 2008 May; 16(5), p. 1099-104.
PMID: 18356841
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Interleukin-22 Genetic Polymorphisms And Risk Of Colon Cancer
Authors: Thompson C.L. , Plummer S.J. , Tucker T.C. , Casey G. , Li L. .
Source: Cancer Causes & Control : Ccc, 2010 Aug; 21(8), p. 1165-70.
PMID: 20339910
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Short Duration Of Sleep Increases Risk Of Colorectal Adenoma
Authors: Thompson C.L. , Larkin E.K. , Patel S. , Berger N.A. , Redline S. , Li L. .
Source: Cancer, 2011-02-15 00:00:00.0; 117(4), p. 841-7.
PMID: 20936662
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Fto Polymorphisms Are Associated With Adult Body Mass Index (bmi) And Colorectal Adenomas In African-americans
Authors: Nock N.L. , Plummer S.J. , Thompson C.L. , Casey G. , Li L. .
Source: Carcinogenesis, 2011 May; 32(5), p. 748-56.
PMID: 21317302
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Racial Differences In Measures Of Obesity And Risk Of Colon Adenoma
Authors: Thompson C.L. , Berger N.A. , Chak A. , Li L. .
Source: Obesity (silver Spring, Md.), 2012 Mar; 20(3), p. 673-7.
PMID: 21996657
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Insulin Resistance, Central Obesity, And Risk Of Colorectal Adenomas
Authors: Ortiz A.P. , Thompson C.L. , Chak A. , Berger N.A. , Li L. .
Source: Cancer, 2012-04-01 00:00:00.0; 118(7), p. 1774-81.
PMID: 22009143
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Concentrations Of Arsenic, Chromium, And Nickel In Toenail Samples From Appalachian Kentucky Residents
Authors: Johnson N. , Shelton B.J. , Hopenhayn C. , Tucker T.T. , Unrine J.M. , Huang B. , Christian W. , Zhang Z. , Shi X. , Li L. .
Source: Journal Of Environmental Pathology, Toxicology And Oncology : Official Organ Of The International Society For Environmental Toxicology And Cancer, 2011; 30(3), p. 213-23.
PMID: 22126614
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Adult Bmi Change And Risk Of Colon Cancer In Postmenopausal Women
Authors: Blake-Gumbs L. , Chen Z. , Thompson C.L. , Berger N.A. , Tucker T.C. , Li L. .
Source: Journal Of Obesity, 2012; 2012, p. 857510.
PMID: 22848798
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Genetic Variation In 15-hydroxyprostaglandin Dehydrogenase And Colon Cancer Susceptibility
Authors: Thompson C.L. , Fink S.P. , Lutterbaugh J.D. , Elston R.C. , Veigl M.L. , Markowitz S.D. , Li L. .
Source: Plos One, 2013; 8(5), p. e64122.
PMID: 23717544
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Meta-analysis Of Mismatch Repair Polymorphisms Within The Cogent Consortium For Colorectal Cancer Susceptibility
Authors: Picelli S. , Lorenzo Bermejo J. , Chang-Claude J. , Hoffmeister M. , Fernández-Rozadilla C. , Carracedo A. , Castells A. , Castellví-Bel S. , Memebers of EPICOLON Consortium-Gastrointestinal Oncology Group of the Spanish Gastroenterological Association , Naccarati A. , et al. .
Source: Plos One, 2013; 8(9), p. e72091.
PMID: 24039736
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Red Meat-derived Heterocyclic Amines Increase Risk Of Colon Cancer: A Population-based Case-control Study
Authors: Helmus D.S. , Thompson C.L. , Zelenskiy S. , Tucker T.C. , Li L. .
Source: Nutrition And Cancer, 2013; 65(8), p. 1141-50.
PMID: 24168237
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Association Between Casp8 -652 6n Del Polymorphism (rs3834129) And Colorectal Cancer Risk: Results From A Multi-centric Study
Authors: Pardini B. , Verderio P. , Pizzamiglio S. , Nici C. , Maiorana M.V. , Naccarati A. , Vodickova L. , Vymetalkova V. , Veneroni S. , Daidone M.G. , et al. .
Source: Plos One, 2014; 9(1), p. e85538.
PMID: 24465592
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High Dietary Glycemic Load Is Associated With Increased Risk Of Colon Cancer
Authors: Zelenskiy S. , Thompson C.L. , Tucker T.C. , Li L. .
Source: Nutrition And Cancer, 2014; 66(3), p. 362-8.
PMID: 24611536
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Discovery Of Common Sequences Absent In The Human Reference Genome Using Pooled Samples From Next Generation Sequencing
Authors: Liu Y. , Koyutürk M. , Maxwell S. , Xiang M. , Veigl M. , Cooper R.S. , Tayo B.O. , Li L. , LaFramboise T. , Wang Z. , et al. .
Source: Bmc Genomics, 2014; 15, p. 685.
PMID: 25129063
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Combined Use Of Vitamin D3 And Metformin Exhibits Synergistic Chemopreventive Effects On Colorectal Neoplasia In Rats And Mice
Authors: Li W. , Wang Q.L. , Liu X. , Dong S.H. , Li H.X. , Li C.Y. , Guo L.S. , Gao J.M. , Berger N.A. , Li L. , et al. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2015 Feb; 8(2), p. 139-48.
PMID: 25416412
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Serum Levels Of Retinol-binding Protein 4 And Risk Of Colon Adenoma
Authors: Abola M.V. , Thompson C.L. , Chen Z. , Chak A. , Berger N.A. , Kirwan J.P. , Li L. .
Source: Endocrine-related Cancer, 2015 Apr; 22(2), p. L1-4.
PMID: 25712946
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Is Retinol Binding Protein 4 A Link Between Adiposity And Cancer?
Authors: Noy N. , Li L. , Abola M.V. , Berger N.A. .
Source: Hormone Molecular Biology And Clinical Investigation, 2015 Aug; 23(2), p. 39-46.
PMID: 26136304
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A Germline Variant On Chromosome 4q31.1 Associates With Susceptibility To Developing Colon Cancer Metastasis
Authors: Markowitz S.D. , Nock N.L. , Schmit S.L. , Stadler Z.K. , Joseph V. , Zhang L. , Willis J.E. , Scacheri P. , Veigl M. , Adams M.D. , et al. .
Source: Plos One, 2016; 11(1), p. e0146435.
PMID: 26751797
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