Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy in the U.S and the rate of CRC is 1.5 times higher in African Americans (AA) than Caucasians. Recent advances in the field of molecular medicine has led to the use of microsatellite instability (MSI), loss of heterozygosity (LOH), and methylation specific PCR techniques which permit detection of chromosomal and gene alterations of colonic mucosal cells. The use of markers has helped to predict disease progression and prognosis. Epigenetic changes are early in the sequence of genetic alterations leading to CRC. Subsequent changes often include the loss of portions or whole chromosomes. MSI in neoplasms accumulates mutations in microsatellites within the coding region of certain genes. These data suggest that MSI, LOH and methylation profiling may add an important layer of information in the molecular phenotyping of malignances for prognostic purposes. We postulate that MSI-H, gene silencing for DNA repair gene hMHL1, p16 and LOH of APC, p53 and deleted in colorectal cancer (DCC), which are known to modulate cellular proliferation in colonic mucosa, may alter chromosome behavior in the pathway of neoplastic transformation. MSI will be measured using five microsatellite loci, and the level of p53, APC and DCC protein will be determined by immunohistochemistry in mucosal biopsies. By determining the methylation and mutation/deletion profiles of 250 cases, we determine specifically (1) to elucidate the effect of p16 and hMLH1 gene methylation in the pathway of neoplastic transformation in normal and cancer tissue of AA patients with CRC, (2) to determine the induction of MSI in colonic mucosa that may be reflected in the expression of biomarkers of neoplastic transformation and cellular proliferation from AA patients history of colonic adenomas, those with no history of adenomas, and those with a history of resected CRC. These experiments may assist in identifying persons at risk of developing adenomas and/or CRC, (3) to determine whether LOH or allelic loss occurs in APC, p53, and DCC genes in normal and cancer tissue of CRC patients and identify persons at risk of developing additional adenomas and/or CRC, (4) to analyze tumor tissue in AA patients with stage III and high-risk stage II CRC who had been treated with fluorouracil, and the ability of MSI and LOH markers to predict survival and/or response to treatment. These studies will help in the detection and profiling of genetic changes in the pathway of CRC in AA.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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General Medicine A Subcommittee 2 (GMA)
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Ogunbiyi, Peter
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Howard University
Internal Medicine/Medicine
Schools of Medicine
United States
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Brim, Hassan; Abu-Asab, Mones S; Nouraie, Mehdi et al. (2014) An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors. PLoS One 9:e82185
Ashktorab, Hassan; Entezari, Omid; Nouraie, Mehdi et al. (2012) Helicobacter pylori protection against reflux esophagitis. Dig Dis Sci 57:2924-8
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Cai, Chunxiao; Ashktorab, Hassan; Pang, Xiaowu et al. (2012) MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in vivo by targeting tumor suppressor CHD5. PLoS One 7:e29750
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Ashktorab, Hassan; Nouri, Zahra; Nouraie, Mehdi et al. (2011) Esophageal carcinoma in African Americans: a five-decade experience. Dig Dis Sci 56:3577-82
Ashktorab, Hassan; Nguza, Bijou; Fatemi, Mehrnaz et al. (2011) Case-control study of vitamin D, dickkopf homolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in African Americans. PLoS One 6:e25314
Brim, Hassan; Kumar, Krishan; Nazarian, Javad et al. (2011) SLC5A8 gene, a transporter of butyrate: a gut flora metabolite, is frequently methylated in African American colon adenomas. PLoS One 6:e20216
Nouraie, Mehdi; Hosseinkhah, Fatemeh; Brim, Hassan et al. (2010) Clinicopathological features of colon polyps from African-Americans. Dig Dis Sci 55:1442-9

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