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.

Public Health Relevance

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 have 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136726-04
Application #
8304808
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Nebeling, Linda C
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$457,798
Indirect Cost
$99,930
Name
Case Western Reserve University
Department
Family Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Pardini, Barbara; Verderio, Paolo; Pizzamiglio, Sara et al. (2014) Association between CASP8 -652 6N del polymorphism (rs3834129) and colorectal cancer risk: results from a multi-centric study. PLoS One 9:e85538
Liu, Yu; Koyut├╝rk, Mehmet; Maxwell, Sean et al. (2014) Discovery of common sequences absent in the human reference genome using pooled samples from next generation sequencing. BMC Genomics 15:685
Zelenskiy, Svetlana; Thompson, Cheryl L; Tucker, Thomas C et al. (2014) High dietary glycemic load is associated with increased risk of colon cancer. Nutr Cancer 66:362-8
Helmus, Drew S; Thompson, Cheryl L; Zelenskiy, Svetlana et al. (2013) Red meat-derived heterocyclic amines increase risk of colon cancer: a population-based case-control study. Nutr Cancer 65:1141-50
Thompson, Cheryl L; Fink, Stephen P; Lutterbaugh, James D et al. (2013) Genetic variation in 15-hydroxyprostaglandin dehydrogenase and colon cancer susceptibility. PLoS One 8:e64122
Picelli, Simone; Lorenzo Bermejo, Justo; Chang-Claude, Jenny et al. (2013) Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility. PLoS One 8:e72091
Thompson, Cheryl L; Berger, Nathan A; Chak, Amitabh et al. (2012) Racial differences in measures of obesity and risk of colon adenoma. Obesity (Silver Spring) 20:673-7
Thompson, Cheryl L; Larkin, Emma K; Patel, Sanjay et al. (2011) Short duration of sleep increases risk of colorectal adenoma. Cancer 117:841-7
Johnson, Nancy; Shelton, Brent J; Hopenhayn, Claudia et al. (2011) Concentrations of arsenic, chromium, and nickel in toenail samples from Appalachian Kentucky residents. J Environ Pathol Toxicol Oncol 30:213-23
Nock, Nora L; Plummer, Sarah J; Thompson, Cheryl L et al. (2011) FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans. Carcinogenesis 32:748-56

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