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Sporadic Colon Cancer: Mismatch Repair Immunohistochemistry and Microsatellite Instability in Omani Subjects

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Abstract

Background Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy in the world, and there are suggestions of a particularly high incidence in the Middle East, including those of African origin. Defects in DNA mismatch repair (MMR) systems are involved in the carcinogenesis of both sporadic and inherited human cancers. We assessed colonic cancers in an attempt to identify tumors with DNA MMR deficiency and microsatellite instability (MSI). Additionally, we tested the ability of cell cycle regulator p16 that effects cell proliferation and can be abrogated by hypermethylation of the promoter region. Methods We reviewed the charts of 756 patients who were referred to the Oman major colonoscopy unit of the Sultan Qaboos University Hospital and Royal Hospital from the years 2000 to 2004. Colon cancer tissue was assayed using immunohistochemistry for expression of hMLH1 and hMSH2, and a panel of five pairs of microsatellite primers (NR21, NR22, NR24, BAT25, and BAT26) for MSI-H analysis and additional dinucleotide markers (D17S250, D5S346, and D2S123) used for MSI-L. The expression status of MMR genes and MSI was correlated with cancer stage, location, and histology. A total of 49 tumors were analyzed for histopathology, MSI, and hMLH1/hMSH2 protein expression analysis. The methylation status of the p16 promoter was determined by methylation-specific polymerase chain reaction (PCR). Results The mean age for the carcinomas was 52.2 years and 53% of the patients were male. The majority of the tumors were left-sided. The information currently available indicates that there is an incidence of 4.7% colon cancer (49/1036) and 12.1% (126/1290) colon adenoma among the cases who underwent colonoscopy at these centers. The rate of MSI-H was 12.2% (n = 6), which appears to be the same as previously reported in literature. Eight of 49 tumors (16.3%) were MMR defective by IHC. Defects in the mismatch repair genes hMLH1 and hMSH2 were found in four (66.7%) and two (33.3%) of CRCs MSI-H cases, respectively. Defects in hMLH1 expression in tumors were commonly associated with moderate differentiation. The p16 promoter was methylated in 4% of tumors. Conclusion This is the first genetic study of CRC in this region of the world to demonstrate the incidence of MSI, p16 methylation, and hMLH1 and MSH2 expression in the Omani population. In addition, a relatively high frequency of CRC in younger age groups was noted, which is an important observation. The left-sided preponderance of MMR defective tumors was mostly associated with hMLH1, and with possible loss of hMSH2 expression, an observation that differs from studies on other populations. In conclusion, although the overall rate of CRC is unknown in this region, the frequency of MSI in CRC in this region appears to be the same as in Caucasians in the USA.

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Abbreviations

MSI-H:

Microsatellite instability-high

MSS:

Microsatellite stable

MSI-L:

Microsatellite instability-low

MMR:

Mismatch repair

HNPCC:

Hereditary nonpolyposis colorectal cancer

TNM:

Tumor nodes metastasis

5FU:

5-Fluorouracil

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Acknowledgements

This work was supported by Grant #CA102681, funded by the National Cancer Institute, NIH and Marcia Johnson award from Howard University. The authors would like to thank Howard University and the Fulbright program for their support of this research project, and the College of Medicine, Health Sciences of Sultan Qaboos University and Royal Hospital in Muscat for access to patient materials and records, and provision of the laboratory facility. Authors’ contributions: HA, SR, and MA designed the project; HB, KA, RA, and MA performed the MSI, IHC, and validation experiments; SSG performed the statistical analysis and consensus sequence matching; AD and MA performed the pathology section of the study for the stage of the tumor end microdissection; HA, DTS, and MK reviewed and contributed to the discussion of the genetic data. All authors contributed to the writing of the manuscript and have read and approved its revised and final drafts.

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Authors and Affiliations

  1. Department of Medicine and Cancer Center, Howard University College of Medicine, 2041 Georgia Avenue, N.W, Washington, DC, 20060, USA

    Hassan Ashktorab, Hassan Brim & Duane T. Smoot

  2. Howard University, Washington, DC, USA

    Hassan Ashktorab & Hassan Brim

  3. Department of Pathology, Howard University, Washington, DC, USA

    Duane T. Smoot

  4. College of Medicine, Sultan Qaboos University, Muscat, Oman

    Marwa Al-Riyami, Anand Date, Kamla Al-Mawaly, Masoud Kashoub, Rayhaneh Al-Mjeni, Mansoor AL-Moundhri, Suleiman Al-Hashemi, Shyam S. Ganguly & Sandy Raeburn

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  1. Hassan Ashktorab
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Correspondence to Hassan Ashktorab.

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Ashktorab, H., Brim, H., Al-Riyami, M. et al. Sporadic Colon Cancer: Mismatch Repair Immunohistochemistry and Microsatellite Instability in Omani Subjects. Dig Dis Sci 53, 2723–2731 (2008). https://doi.org/10.1007/s10620-007-0189-3

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  • DOI: https://doi.org/10.1007/s10620-007-0189-3

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