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.
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.
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|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|
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|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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