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.