Over a lifetime, roughly 5% of Americans develop colorectal cancer, and more than a third do not survive the disease. Colorectal cancer begins to develop when cells in the lining of the lower intestine suffer genetic mutations that cause growth and proliferation into a colorectal polyp. If not removed, this pre-cancerous growth eventually develops into a malignant tumor. One common type of mutation, found in approximately 80% of colorectal cancers, causes defects the APC protein, named after the inherited syndrome of colon cancer predisposition familial adenomatous polyposis coli. Defects in this protein trigger the formation of a polyp. It is critical to identify how APC deficiency enables a polyp to form andprogress into cancer in order to develop new therapeutic strategies for tumor prevention and treatment. Recent studies have shown that APC, a cytoplasmic and nuclear protein with DNA-binding capability, binds an enhancer site upstream of the MYC proto-oncogene, a known Wnt target, to downregulate its transcription directly (Sierra et al., 2006). We hypothesize that APC similarly regulates other targets relevant to tumorigenesis, and that the 80% of colorectal cancers that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 20% of colorectal cancers. This could potentially cause these two groups of cancers to respond differently to chemotherapy, and may help explain why certain therapies benefit some patients but not others. Our preliminary genomic and informatics data show that in colorectal cancer cells with activated Wnt signaling but intact APC, the loss of APC causes abnormal activation or suppression of nearly 200 genes. These proposed studies will identify which of those genes are truly controlled by the interaction of APC with DNA, the mechanism by which APC controls them, and which of them are important for tumor development. Patient tumor samples of different stages and grades will be tested for activation or suppression of these genes. If changes in certain genes are associated with clinical phenotypes, then testing for these changes in patients may lead to more accurate prognosis and improve treatment decisions. Genes activated or suppressed by APC can be targeted by new drugs developed against APC-deficient colorectal cancers.

Public Health Relevance

This project will investigate the recently-discovered function of the APC tumor suppressor as a chromatin- interacting protein which regulates gene expression in the cells that line the large intestine. Disruption of this function by APC mutations may contribute to the abnormal gene expression that drives the formation of polyps and the development of colorectal cancer. By identifying the disrupted genes and studying their usage across the stages of cancer development; we will characterize their potential as markers for disease severity or as targets for future therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA174260-01
Application #
8457789
Study Section
Special Emphasis Panel (ZRG1-F09-P (20))
Program Officer
Schmidt, Michael K
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$37,414
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210