Colorectal cancer (CRC) is a common disease but disproportionately adversely affects African Americans over other racial groups, with younger age of presentation, a more advanced stage, and higher mortality. The reason for this adverse outcome is not clear. We show in preliminary data that CRCs from African Americans from a population-based cohort have a lower prevalence of microsatellite instability (MSI, caused by "major" DNA mismatch repair [MMR] deficiency), a biomarker associated with better survival presumably due to surrounding immune cells, but have a higher prevalence of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a biomarker we show associated with adenoma-to-carcinoma progression, advanced staged cancers, and higher degrees of tumor immune cell infiltration. EMAST appears to be an acquired defect in colorectal tumors that may be a result of tumor inflammation, and is associated with heterogeneous loss of expression of the "minor" MMR protein hMSH3. We hypothesize that the immune cell profiles from MSI tumors are different than EMAST tumors (low and high prevalence among African Americans, respectively). In this proposal, we will explore racial differences in immune profiles within colorectal cancers, including survival prognostication, utilizing samples and data from the North Carolina Colon Cancer Study, the North Carolina Rectal Cancer Study, the Colon Cancer Family Registry, as well as other specimens. We will examine the immune profiles of EMAST and MSI tumors to help determine the type of immune cells associated with each biomarker. We will also compare immune profiles between race and genomic instability to further correlate differences. The information obtained from work in this proposal may explain some of the racial differences observed in colorectal cancer, and direct future investigation on differences between acquired "minor" and "major" MMR defects on activating the immune system.

Public Health Relevance

Colorectal cancers present more advanced and have higher mortality among African Americans, with reasons unclear. The prevalence of two forms of biomarkers from African American tumors favor lower survival. We aim to determine the type of immune cells associated with each biomarker so as to explain some of the racial differences observed in colorectal cancer, and which will also provide clues to how these biomarkers might attract the immune cells into the tumor, a finding that might be replicated to improve patient survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA162147-02
Application #
8538900
Study Section
Special Emphasis Panel (ZRG1-OBT-A (55))
Program Officer
Okano, Paul
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$277,250
Indirect Cost
$60,157
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Carethers, John M (2016) GRG Profiles: John M. Carethers. Dig Dis Sci 61:1429-35
Koi, Minoru; Garcia, Melissa; Choi, Chan et al. (2016) Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. Gastroenterology 150:944-55
Basa, Ranor C B; Davies, Vince; Li, Xiaoxiao et al. (2016) Decreased Anti-Tumor Cytotoxic Immunity among Microsatellite-Stable Colon Cancers from African Americans. PLoS One 11:e0156660
Carethers, John M; Goel, Ajay (2016) Presentation of the Julius M. Friedenwald Medal to C. Richard Boland, MD, AGAF. Gastroenterology 150:1673-7
Suzuki, Satoshi; Iwaizumi, Moriya; Tseng-Rogenski, Stephanie et al. (2016) Production of truncated MBD4 protein by frameshift mutation in DNA mismatch repair-deficient cells enhances 5-fluorouracil sensitivity that is independent of hMLH1 status. Cancer Biol Ther 17:760-8
Carethers, John M (2016) Facilitating Minority Medical Education, Research, and Faculty. Dig Dis Sci 61:1436-9
Ashktorab, Hassan; Ahuja, Sadhna; Kannan, Lakshmi et al. (2016) A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget 7:34546-57
Fearon, Eric R; Carethers, John M (2015) Molecular subtyping of colorectal cancer: time to explore both intertumoral and intratumoral heterogeneity to evaluate patient outcome. Gastroenterology 148:10-3
Carethers, John M (2015) Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. Dig Dis Sci 60:711-21
Carethers, John M; Braun, Jonathan; Sands, Bruce E (2015) Genetics, Genetic Testing, and Biomarkers of Digestive Diseases. Gastroenterology 149:1131-3

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