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High Incidence of Microsatellite Instability in Colorectal Cancer from African Americans¹

Cancer Center and Department of Medicine [H. A., D. T. S., M. R., E. N., S. S.], National Human Genome Center at Howard University and Department of Microbiology [R. K., G. V., M. D.], and Department of Pathology [T. N.], Howard University Washington, DC 20060; Applied Statistics, Department of Natural Resource Sciences, University of Maryland, College Park, Maryland [B. M.]; Department of Medicine and Cancer Center, University of California San Diego, San Diego, California [J. M. C.]; San Diego Veterans Administration Healthcare System, San Diego, California [J. M. C.]; and Department of Medicine and Oncology, The Johns Hopkins University, Baltimore, Maryland [F. M. G.]

Purpose: Colorectal carcinoma (CRC) is the second most common cause of cancer death in the United States, and the rate of CRC is nearly 1.5 times higher in African-Americans (AA) than in Caucasians. Microsatellite instability (MSI) is observed in sporadic CRC reflecting promoter hypermethylation of the DNA mismatch repair gene hMLH1, and anecdotal evidence suggests an increased incidence of MSI among AAs. Additionally, p16 can be inactivated by hypermethylation of the promoter region, abrogating its ability to regulate cell proliferation. The objective of this study is to determine the frequency of MSI and p16 gene methylation in CRC from AA patients.

Experimental Design: Experiments were conducted on serially collected archival samples of colon cancer and adjacent normal tissue (n = 22). Five microsatellite markers were used to measure MSI in tumors with direct comparison to normal tissue from the same patient. p16 promoter methylation status was determined by methylation-specific PCR.

Results: Ten cancers (45%) demonstrated high MSI (MSI-H), 1 demonstrated low MSI, and the remaining 11 tumors were microsatellite stable. Most of the MSI-H tumors were proximal, well differentiated, and showed high levels of mucin production. Most patients in the MSI-H group were female (70%), whereas most of the microsatellite-stable group (81%) were male. Five of the 22 tumors (22%) had methylation of the p16 promoter.

Conclusion: Data provided here demonstrated that the incidence of MSI-H tumors was 3-fold higher in our study group of AA patients compared with data reported in nonracially selected but serially collected studies. Odds ratio analysis indicates that the chance of female patients having MSI-H was 11.7 times more than male patients (P < 0.03). The reason for this gender difference is unknown. These findings might reflect dietary differences or genetic polymorphisms that may be common in the AA population. Additional investigation in a larger patient population is needed before strong conclusion can be drawn.

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