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 #
1U01CA162147-01A1
Application #
8289085
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
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$312,881
Indirect Cost
$79,321
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
Tseng-Rogenski, Stephanie S; Hamaya, Yasushi; Choi, Daniel Y et al. (2015) Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology 148:579-89
Carethers, John M; Murali, Bhavya; Yang, Bing et al. (2014) Influence of race on microsatellite instability and CD8+ T cell infiltration in colon cancer. PLoS One 9:e100461
Carethers, John M (2014) Differentiating Lynch-like from Lynch syndrome. Gastroenterology 146:602-4
Kinseth, Matthew A; Jia, Zhenyu; Rahmatpanah, Farahnaz et al. (2014) Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes. Int J Cancer 134:81-91
Carethers, John M (2014) DNA testing and molecular screening for colon cancer. Clin Gastroenterol Hepatol 12:377-81
Ashktorab, Hassan; Rahi, Hamed; Wansley, Daniel et al. (2013) Toward a comprehensive and systematic methylome signature in colorectal cancers. Epigenetics 8:807-15
Iwaizumi, Moriya; Tseng-Rogenski, Stephanie; Carethers, John M (2013) Acidic tumor microenvironment downregulates hMLH1 but does not diminish 5-fluorouracil chemosensitivity. Mutat Res 747-748:19-27