Genetic, clinical and molecular characterization of inherited colon cancer risk is the focus of our present and long-term work. Genes for the rare syndromes of this malignancy have been found but account for only a small fraction of the estimated one-third of colon cancer cases that arise from inheritance.
The aims of our present proposal are 1) to identify the susceptibility genes that give rise to the more common inherited risk, 2) to continue to define the associated phenotype, 3) to establish molecular characteristics of the high-risk families and known syndromes with gene expression profiling and 4) to examine the expression of specific APC/beta-catenin pathway genes as potential diagnostic markers. Together these goals will provide tools to identify persons with inherited risk. We will accomplish the aims as follows: We will identify colon cancer susceptibility loci by linkage analysis of large high-risk colon cancer families in which the known syndromes of colon cancer have been ruled out. Colonoscopy is performed on family members to define polyp expression, both for phenotype and linkage analysis. Gene expression profiling by microarray analysis is performed on normal appearing and neoplastic colonic tissue obtained at colonoscopy and immediately preserved. Profiling will assist both in identification of susceptibility pathways and in establishing characteristic expression profiles in the inherited colon cancer settings. Gene expression patterns will be examined in the normal and neoplastic tissue of the high-risk families and compared to similar samples from families with familial adenomatous polyposis (FAP), attenuated FAP, hereditary nonpolyposis colorectal cancer, sporadic adenomatous polyp cases and normal controls. Gene expression will be examined using a reference RNA and analyzed by supervised (and later unsupervised) analysis of the groups. Finally the expression of four specific APC/beta-catenin pathway marker genes will be examined in neoplastic and normal tissues from the above groups by both real-time quantitative PCR and by in situ RNA hybridization. Previous microarray experiments in our laboratory indicate that expression of these genes is frequently perturbed in sporadic polyps, making them attractive markers of cancer susceptibility to evaluate APC/beta-catenin pathway contributions in undefined forms of inherited colon cancer, as compared to defined inherited syndromes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040641-20
Application #
7018538
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Seminara, Daniela
Project Start
1985-09-01
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
20
Fiscal Year
2006
Total Cost
$385,270
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
Jewel Samadder, N; Valentine, John F; Guthery, Stephen et al. (2017) Colorectal Cancer in Inflammatory Bowel Diseases: A Population-Based Study in Utah. Dig Dis Sci 62:2126-2132
Samadder, N Jewel; Curtin, Karen; Pappas, Lisa et al. (2016) Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol 14:279-86.e1-2
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2016) Familial Risk in Patients With Carcinoma of Unknown Primary. JAMA Oncol 2:340-6
Samadder, N Jewel; Jasperson, Kory; Burt, Randall W (2015) Hereditary and common familial colorectal cancer: evidence for colorectal screening. Dig Dis Sci 60:734-47
Snow, A K; Tuohy, T M F; Sargent, N R et al. (2015) APC promoter 1B deletion in seven American families with familial adenomatous polyposis. Clin Genet 88:360-5
Samadder, N J; Smith, K R; Mineau, G P et al. (2015) Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah. Aliment Pharmacol Ther 41:573-80
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2015) Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis. Clin Gastroenterol Hepatol 13:2305-11.e1-2
Samadder, N Jewel; Curtin, Karen; Wong, Jathine et al. (2014) Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah. Clin Gastroenterol Hepatol 12:2078-84.e1-2
Samadder, N Jewel; Curtin, Karen; Tuohy, Thérèse M F et al. (2014) Characteristics of missed or interval colorectal cancer and patient survival: a population-based study. Gastroenterology 146:950-60
Tuohy, Thérèse M F; Rowe, Kerry G; Mineau, Geraldine P et al. (2014) Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah. Cancer 120:35-42

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