Differing DNA Methylation Patterns and Gene Mutation Frequencies in Colorectal Carcinomas from Middle Eastern Countries

Abstract

Purpose: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. Experimental Design: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. Results: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings inTurkish colorectal carcinoma were most similar to those reported forWestern cases. Conclusions: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.The epidemiology of colorectal carcinoma in developing countries differs from that of developed countries. Colorectal carcinoma in developing countries, including those in the Middle East, is usually characterized by low incidence, young age of onset, left-sided location, poor differentiation, and paucity of precursor adenomas (1 -9). International studies as well as studies in immigrants suggest that environmental factors, especially lifestyle and dietary differences, play a major part in the observed epidemiologic differences.Morphologic and genetic progression to colorectal carcinoma in an adenoma-adenocarcinoma sequence and in hereditary colorectal carcinoma syndromes are well described (reviewed in ref. 10). Chromosomal instability and mutation of the K-ras proto-oncogene and the p53 suppressor gene are common.

The prognostic value of c‐Kit, K‐ras codon 12, and p53 codon 72 mutations in Egyptian patients with stage II colorectal cancer

“…Although, in the current study, the frequency of p53 overexpression (54.6%) and mutation (36%) was within the universally reported range, 7,36,38 the spectrum of p53 mutations reported in our Egyptian patients differed from the data reported in Western countries and the United States on several points, including 1) the high rate of multiple mutations occurring in the same patient (9 of 29 mutations), which also was reported by Akkiprik et al 7 in patients with CRC from Turkey; and 2) the mutational hotspot at exon 4 (codon 72), which was not reported previously in patients with CRC from Western countries. However codon 72 polymorphism (arginine-proline) have been reported in other solid tumors.…”

“…7,14,15,38,45 Such a wide range was attributed to tumor storage methods, the techniques used to assess mutations, tumor heterogeneity, or the specific features of patient cohorts in the study. However, the reported K-ras mutation rates do not exceed 50%, suggesting the presence of alternative pathway(s) in colorectal carcinogenesis.…”

Evaluation of candidate methylation markers to detect cervical neoplasia

“…Standard or conventional PCR may thus result in higher methylation frequencies due to the lack of specificity. Reasons for discrepancy by cell type are more difficult to explain although the combination of using different assays, having varying and usually small sizes, and geographically different patient populations [26][27][28] are possibilities.…”

Correlation of Vascular Endothelial Growth Factor Expression and Neovascularization with Colorectal Carcinoma: A Pilot Study

“…Soliman et al [15] and Chan et al [16] revealed that CRC in Egypt has no age predilection and more than one-third of tumors affect a young population. The high prevalence in young people can neither be explained on a hereditary basis nor can it be attributed to bilharziasis.…”