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 #
4U01CA162147-05
Application #
9136652
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okano, Paul
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
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
Bhaskaran, Nitya; Luu, Jennifer; Kelley, Scott T et al. (2018) A new method for discovering EMAST sequences in animal models of cancer. Sci Rep 8:13764
Koi, Minoru; Tseng-Rogenski, Stephanie S; Carethers, John M (2018) Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer. World J Gastrointest Oncol 10:1-14
Carethers, John M (2017) Microsatellite Instability Pathway and EMAST in Colorectal Cancer. Curr Colorectal Cancer Rep 13:73-80
Ashktorab, Hassan; Kupfer, Sonia S; Brim, Hassan et al. (2017) Racial Disparity in Gastrointestinal Cancer Risk. Gastroenterology 153:910-923
Carethers, John M (2016) HEREDITARY, SPORADIC AND METASTATIC COLORECTAL CANCER ARE COMMONLY DRIVEN BY SPECIFIC SPECTRUMS OF DEFECTIVE DNA MISMATCH REPAIR COMPONENTS. Trans Am Clin Climatol Assoc 127:81-97
Ashktorab, Hassan; Ahuja, Sadhna; Kannan, Lakshmi et al. (2016) A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget 7:34546-57
Carethers, John M (2016) Facilitating Minority Medical Education, Research, and Faculty. Dig Dis Sci 61:1436-9
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
Carethers, John M (2016) The Increasing Incidence of Colorectal Cancers Diagnosed in Subjects Under Age 50 Among Races: CRaCking the Conundrum. Dig Dis Sci 61:2767-2769
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

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