High incidence of microsatellite instability in colorectal cancer from African Americans

Hassan Ashktorab, Duane T. Smoot, John M. Carethers, Majid Rahmanian, Rick A Kittles, Greg Vosganian, Menaham Doura, Emmanel Nidhiry, Tammy Naab, Bahram Momen, Shahed Shakhani, Francis M. Giardiello

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1112-1117
Number of pages6
JournalClinical Cancer Research
Volume9
Issue number3
StatePublished - Mar 1 2003
Externally publishedYes

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Microsatellite Instability
African Americans
Colorectal Neoplasms
Incidence
Methylation
Neoplasms
Microsatellite Repeats
p16 Genes
DNA Mismatch Repair
Mucins
Genetic Polymorphisms
Genetic Promoter Regions
Colonic Neoplasms
Population
Cause of Death
Research Design
Odds Ratio
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ashktorab, H., Smoot, D. T., Carethers, J. M., Rahmanian, M., Kittles, R. A., Vosganian, G., ... Giardiello, F. M. (2003). High incidence of microsatellite instability in colorectal cancer from African Americans. Clinical Cancer Research, 9(3), 1112-1117.

High incidence of microsatellite instability in colorectal cancer from African Americans. / Ashktorab, Hassan; Smoot, Duane T.; Carethers, John M.; Rahmanian, Majid; Kittles, Rick A; Vosganian, Greg; Doura, Menaham; Nidhiry, Emmanel; Naab, Tammy; Momen, Bahram; Shakhani, Shahed; Giardiello, Francis M.

In: Clinical Cancer Research, Vol. 9, No. 3, 01.03.2003, p. 1112-1117.

Research output: Contribution to journalArticle

Ashktorab, H, Smoot, DT, Carethers, JM, Rahmanian, M, Kittles, RA, Vosganian, G, Doura, M, Nidhiry, E, Naab, T, Momen, B, Shakhani, S & Giardiello, FM 2003, 'High incidence of microsatellite instability in colorectal cancer from African Americans', Clinical Cancer Research, vol. 9, no. 3, pp. 1112-1117.
Ashktorab H, Smoot DT, Carethers JM, Rahmanian M, Kittles RA, Vosganian G et al. High incidence of microsatellite instability in colorectal cancer from African Americans. Clinical Cancer Research. 2003 Mar 1;9(3):1112-1117.
Ashktorab, Hassan ; Smoot, Duane T. ; Carethers, John M. ; Rahmanian, Majid ; Kittles, Rick A ; Vosganian, Greg ; Doura, Menaham ; Nidhiry, Emmanel ; Naab, Tammy ; Momen, Bahram ; Shakhani, Shahed ; Giardiello, Francis M. / High incidence of microsatellite instability in colorectal cancer from African Americans. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 3. pp. 1112-1117.
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abstract = "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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AU - Ashktorab, Hassan

AU - Smoot, Duane T.

AU - Carethers, John M.

AU - Rahmanian, Majid

AU - Kittles, Rick A

AU - Vosganian, Greg

AU - Doura, Menaham

AU - Nidhiry, Emmanel

AU - Naab, Tammy

AU - Momen, Bahram

AU - Shakhani, Shahed

AU - Giardiello, Francis M.

PY - 2003/3/1

Y1 - 2003/3/1

N2 - 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.

AB - 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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