Colorectal cancer has many diet and lifestyle factors that contribute to the etiology. Data suggest that differences in etiology exist by tumor site, age, and sex, and that certain exposures modify the effects of others, indicating the importance of various diet and lifestyle factors in certain environments. Major factors that modify the effects of other risk factors are'use of aspirin and ibuprofen-type drugs. Our previous data have shown that NSAIDs interact with a variety of diet and lifestyle factors, including dietary fat, BMI, insulin- related genes, and estrogen. We hypothesize that genetic variation in an inflammation-related signaling pathway and in a pathway where inflammation, insulin and estrogen converge (designated as a metabolic signaling pathway) will most likely have implications for disease risk. We propose to study two pathways which have not previously been studied with colorectal cancer. We utilize data previously collected on 2780 incident cases of colorectal cancer and 3025 population-based controls to obtain a better understanding of the inter-relationship between inflammation, insulin, and estrogen. We examine known functional polymorphisms and evaluate haplotypes in candidate genes in an inflammation-related pathway (IL6, IL8, IL10, NFKB, TNF-A, IL4, IL1, ILIRA and IFNG) and genes located at key junctions where other cellular signaling pathways converge which we describe as a metabolic signaling pathway (SOC1, SOC2, AKT, FRAP1 (mTOR), TSC1, TSC2, P13K, LKB, AMP, PTEN, S6K.VEGF, STAT1, STAT6, JNK1, and pSSMAPK). We will test associations between genetic polymorphisms and haplotypes of these genes with colorectal cancer. We will evaluate the interaction of these genes with NSAIDs/aspirin, estrogen, BMI, dietary fat, antioxidants, and physical activity. We will evaluate associations of these polymorphisms/haplotypes with specific types of tumor mutations. We will utilize statistical methods to gain insight into how these genes relate to specific disease pathways and how genes inter-relate along these pathways. We include test of functionality for all genes and SNPs identified as being assocatied with CRC and we will validate study findings using statistical techniques that allow for test and validation. Identification of polymorphisms or haplotypes that are relevant to colorectal cancer will advance our understanding of etiology, may lead to specific health recommendations, and can identify targets for drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048998-16
Application #
8120975
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Su, Joseph
Project Start
1991-03-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
16
Fiscal Year
2011
Total Cost
$899,545
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Mullany, Lila E; Herrick, Jennifer S; Wolff, Roger K et al. (2017) Alterations in microRNA expression associated with alcohol consumption in rectal cancer subjects. Cancer Causes Control 28:545-555
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Slattery, Martha L; Herrick, Jennifer S; Mullany, Lila E et al. (2017) The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. Genes Chromosomes Cancer 56:769-787
Slattery, Martha L; Trivellas, Andromahi; Pellatt, Andrew J et al. (2017) Genetic variants in the TGF?-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue. Oncotarget 8:16765-16783
Stevens, John R; Herrick, Jennifer S; Wolff, Roger K et al. (2017) Identifying factors associated with the direction and significance of microRNA tumor-normal expression differences in colorectal cancer. BMC Cancer 17:707

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