Colorectal cancer (CRC) is a significant cause of cancer morbidity and mortality affecting almost 150,000 Americans yearly. African Americans have the highest CRC incidence and mortality of all US populations. These disparities have not been explained, and biological risk factors including genetic susceptibility to CRC are understudied in African Americans. I am a gastroenterologist who seeks to develop a career as an independent translational physician-scientist in CRC genetics. My long-term career goals require me to obtain additional training in: 1) molecular and statistical genetics;and 2) cancer biology. The 5-year career development program described in this application will take place at the University of Chicago which distinguishes itself in the field of human and cancer genetics especially in admixed populations. I am fortunate to have key collaborators at the University of North Carolina and the University of Illinois Chicago, and together we have DNA from over 1000 African American CRC patients and 1000 African American control subjects available for my proposed study. Dr. Nancy Cox, Professor of Medicine and Chief of Human Genetics, is my mentor and will provide expertise in statistical genetics. Dr. Nathan Ellis, Associate Professor of Medicine, is a co-mentor and will provide expertise in CRC molecular genetics. An inter-disciplinary Advisory Committee comprised of Dr. Rick Kittles, an expert in genetics of admixed populations, Dr. Olufunmilayo Olopade, an internationally recognized leader in cancer genetics, and Dr. Eugene Chang, a successful physician-scientist in gastroenterology, will guide and advise me during this development period. The broad objectives of this research proposal are the identification of genetic susceptibility factors that contribute to risk of CRC development in African Americans. I will study single nucleotide polymorphisms (SNPs) discovered using genome-wide association studies in European populations. Regions containing these SNP are likely to harbor functional variants. African Americans are an ideal population in whom to identify functional variants because their genomes exhibit less linkage disequilibrium. To this end, I propose three specific aims: 1) Validate candidate CRC-associated regions in African American cases and controls;2) Discover novel SNPs in CRC-associated regions by targeted resequencing using next-generation sequencing technologies;and 3) Identify putative functional variants in candidate CRC-associated regions that can be further evaluated in future functional studies. By the end of my career development period, I will be uniquely equipped to undertake further translational research in CRC genetics. My long-term research goals are to understand genetic susceptibility in CRC pathogenesis and to study how genetic susceptibility factors can be used to risk stratify individuals for CRC screening and thereby prevent disease especially in high risk but understudied populations like African Americans.

Public Health Relevance

Of all US populations, African Americans have the highest incidence and mortality of colorectal cancer. Reasons for these differences are not explained, and hereditary factors have not been extensively studied in this high risk population. The goal of our study is to better understand hereditary factors that increase risk of colorectal cancer especially in African-Americans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA142892-04
Application #
8533768
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2010-09-17
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$164,376
Indirect Cost
$12,176
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Hulur, Imge; Gamazon, Eric R; Skol, Andrew D et al. (2015) Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics 16:138
Kupfer, Sonia S; Carr, Rotonya M; Carethers, John M (2015) Reducing colorectal cancer risk among African Americans. Gastroenterology 149:1302-4
Guindalini, Rodrigo Santa Cruz; Win, Aung Ko; Gulden, Cassandra et al. (2015) Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology 149:1446-53
Pibiri, Fabio; Kittles, Rick A; Sandler, Robert S et al. (2014) Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control 25:561-70
Cohn, Aaron; Sofia, Anthony M; Kupfer, Sonia S (2014) Type 1 diabetes and celiac disease: clinical overlap and new insights into disease pathogenesis. Curr Diab Rep 14:517
Maranville, Joseph C; Micic, Dejan; Hanauer, Stephen B et al. (2014) In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease. J Crohns Colitis 8:1539-47
Appannagari, Anoop; Mangla, Shikha; Liao, Chuanhong et al. (2014) Risk factors for inadequate colonoscopy bowel preparations in African Americans and whites at an urban medical center. South Med J 107:220-4
Kupfer, Sonia S; Skol, Andrew D; Hong, Ellie et al. (2014) Shared and independent colorectal cancer risk alleles in TGFβ-related genes in African and European Americans. Carcinogenesis 35:2025-30
Mapes, Brandon; Chase, Meredith; Hong, Ellie et al. (2014) Ex vivo culture of primary human colonic tissue for studying transcriptional responses to 1α,25(OH)2 and 25(OH) vitamin D. Physiol Genomics 46:302-8
Kupfer, Sonia S; Maranville, Joseph C; Baxter, Shaneen S et al. (2013) Comparison of cellular and transcriptional responses to 1,25-dihydroxyvitamin d3 and glucocorticoids in peripheral blood mononuclear cells. PLoS One 8:e76643

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