title: Sporadic colon cancer: mismatch repair immunohistochemistry and microsatellite instability in Omani subjects.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, 2041 Georgia Avenue, N.W, Washington, DC 20060, USA. hashktorab@howard.edu
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashktorab
authors.forename: Hassan
authors.initials: H
authors.lastname: Brim
authors.forename: Marwa
authors.initials: M
authors.lastname: Al-Riyami
authors.forename: Anand
authors.initials: A
authors.lastname: Date
authors.forename: Kamla
authors.initials: K
authors.lastname: Al-Mawaly
authors.forename: Masoud
authors.initials: M
authors.lastname: Kashoub
authors.forename: Rayhaneh
authors.initials: R
authors.lastname: Al-Mjeni
authors.forename: Duane T
authors.initials: DT
authors.lastname: Smoot
authors.forename: Mansoor
authors.initials: M
authors.lastname: Al-Moundhri
authors.forename: Suleiman
authors.initials: S
authors.lastname: Al-Hashemi
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Ganguly
authors.forename: Sandy
authors.initials: S
authors.lastname: Raeburn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009850:Oman; D012189:Retrospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009077:Mucins; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein