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Grant Details

Grant Number: 5R01CA136726-04 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: 2012
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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

High dietary glycemic load is associated with increased risk of colon cancer.
Authors: Zelenskiy S, Thompson CL, Tucker TC, Li L
Source: Nutr Cancer, 2014;66(3), p. 362-8.
EPub date: 2014 Mar 10.
PMID: 24611536
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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 MV, Naccarati A, Vodickova L, Vymetalkova V, Veneroni S, Daidone MG, Ravagnani F, Bianchi T, Bujanda L, Carracedo A, Castells A, Ruiz-Ponte C, Morreau H, Howarth K, Jones A, Castellví-Bel S, Li L, Tomlinson I, Van Wezel T, Vodicka P, Radice P, Peterlongo P, EPICOLON Consortium
Source: PLoS One, 2014;9(1), p. e85538.
EPub date: 2014 Jan 21.
PMID: 24465592
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Red meat-derived heterocyclic amines increase risk of colon cancer: a population-based case-control study.
Authors: Helmus DS, Thompson CL, Zelenskiy S, Tucker TC, Li L
Source: Nutr Cancer, 2013;65(8), p. 1141-50.
EPub date: 2013 Oct 29.
PMID: 24168237
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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, Pardini B, Vodickova L, Müller H, Talseth-Palmer BA, Stibbard G, Peterlongo P, Nici C, Veneroni S, Li L, Casey G, Tenesa A, Farrington SM, Tomlinson I, Moreno V, van Wezel T, Wijnen J, Dunlop M, Radice P, Scott RJ, Vodicka P, Ruiz-Ponte C, Brenner H, Buch S, Völzke H, Hampe J, Schafmayer C, Lindblom A
Source: PLoS One, 2013;8(9), p. e72091.
EPub date: 2013 Sep 6.
PMID: 24039736
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Genetic variation in 15-hydroxyprostaglandin dehydrogenase and colon cancer susceptibility.
Authors: Thompson CL, Fink SP, Lutterbaugh JD, Elston RC, Veigl ML, Markowitz SD, Li L
Source: PLoS One, 2013;8(5), p. e64122.
EPub date: 2013 May 22.
PMID: 23717544
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Adult BMI Change and Risk of Colon Cancer in Postmenopausal Women.
Authors: Blake-Gumbs L, Chen Z, Thompson CL, Berger NA, Tucker TC, Li L
Source: J Obes, 2012;2012, p. 857510.
EPub date: 2012 Jul 9.
PMID: 22848798
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Concentrations of arsenic, chromium, and nickel in toenail samples from Appalachian Kentucky residents.
Authors: Johnson N, Shelton BJ, Hopenhayn C, Tucker TT, Unrine JM, Huang B, Christian W, Zhang Z, Shi X, Li L
Source: J Environ Pathol Toxicol Oncol, 2011;30(3), p. 213-23.
PMID: 22126614
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Insulin resistance, central obesity, and risk of colorectal adenomas.
Authors: Ortiz AP, Thompson CL, Chak A, Berger NA, Li L
Source: Cancer, 2012 Apr 1;118(7), p. 1774-81.
EPub date: 2011 Aug 25.
PMID: 22009143
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Racial differences in measures of obesity and risk of colon adenoma.
Authors: Thompson CL, Berger NA, Chak A, Li L
Source: Obesity (Silver Spring), 2012 Mar;20(3), p. 673-7.
EPub date: 2011 Oct 13.
PMID: 21996657
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FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans.
Authors: Nock NL, Plummer SJ, Thompson CL, Casey G, Li L
Source: Carcinogenesis, 2011 May;32(5), p. 748-56.
EPub date: 2011 Feb 11.
PMID: 21317302
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Short duration of sleep increases risk of colorectal adenoma.
Authors: Thompson CL, Larkin EK, Patel S, Berger NA, Redline S, Li L
Source: Cancer, 2011 Feb 15;117(4), p. 841-7.
EPub date: 2010 Oct 8.
PMID: 20936662
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Interleukin-22 genetic polymorphisms and risk of colon cancer.
Authors: Thompson CL, Plummer SJ, Tucker TC, Casey G, Li L
Source: Cancer Causes Control, 2010 Aug;21(8), p. 1165-70.
EPub date: 2010 Mar 26.
PMID: 20339910
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Associations between obesity and changes in adult BMI over time and colon cancer risk.
Authors: Nock NL, Thompson CL, Tucker TC, Berger NA, Li L
Source: Obesity (Silver Spring), 2008 May;16(5), p. 1099-104.
EPub date: 2008 Mar 6.
PMID: 18356841
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