Distinct Genetic and Epigenetic Signatures of Colorectal Cancers According to Ethnic Origin

BACKGROUND: The outcome of colorectal cancer varies depending on ethnic origin. Egyptian colorectal carcinoma is surprisingly young-age disease with high proportion of rectal and advanced stage cancers. METHODS: We characterized 69 sporadic Egyptian colorectal cancers for promoter methylation at 24 tumor suppressor genes, microsatellite instability, and expression of mismatch repair, p53, and β-catenin proteins. Data were compared with 80 Western colorectal carcinoma of sporadic and familial origin from Finland. RESULTS: Egyptian colorectal carcinomas showed significantly higher methylation of the microsatellite stable (MSS) tumors as reflected by the average number of methylated genes per case (P = 0.00002) and tumor suppressor gene methylator phenotype (TSGMP), defined here as methylation of ≥ 5 genes, (P = 0.0001) compared with the sporadic Western cancers. The TSGMP was associated with advanced stage in the Egyptian cancers (P = 0.0016). Four genes were differentially methylated between Egyptian and Western cases, of which the association of CDKN2B/p15 methylation with Egyptian origin was outstanding (P = 4.83 E-10). Egyptian carcinoma also showed significantly lower frequency of nuclear β-catenin localization than the sporadic Western cancers (P = 0.00006) but similar to that of the familial Western subset designated as familial colorectal cancer type X. CONCLUSIONS: We show novel pathway in colon carcinogenesis marked by high methylation of MSS cancers, remarkable CDKN2B/p15 methylation, and low frequency of Wnt signaling activation. IMPACT: Our findings highlight the possible effect of environmental exposures in carcinogenesis through DNA methylation and should have applications in prevention, molecular diagnosis, prognosis, and treatment.