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

Authors' Affiliations: ¹ Department of Pathology, Division of Pathology and Laboratory Medicine; ² Department of Epidemiology, ³ Division of Cancer Prevention; ⁴ Department of Leukemia, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁵ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan; Departments of ⁶ Pathology and ⁷ Surgical Oncology, The National Cancer Institute of Cairo University, Cairo, Egypt; Departments of ⁸ Pathology and ⁹ Surgery, Jordan University for Science and Technology, Irbid, Jordan; ¹⁰ Department of Genetics, Institute for Experimental Medicine; ¹¹ Department of Pathology, Faculty of Medicine, Istanbul University, Istanbul, Turkey; and ¹² Department of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China

Requests for reprints: Stanley R. Hamilton, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX 77030. Phone: 713-792-2040; Fax: 713-792-4094; E-mail: shamilto{at}mdanderson.org.

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 in Turkish colorectal carcinoma were most similar to those reported for Western 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.