||5R01CA136726-04 Interpret this number
||Case Western Reserve University
||Obesity-Related Insulin Resistance Signaling Pathway Factors and Colon Cancer
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.
Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility.
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
PLoS One, 2013 Sep 6;8(9), p. e72091.
2013 Sep 6.
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