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

Abstract

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 b-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 ¼ 0.00002) and tumor suppressor gene methylator phenotype (TSGMP), defined here as methylation of !5 genes, (P ¼ 0.0001) compared with the sporadic Western cancers. The TSGMP was associated with advanced stage in the Egyptian cancers (P ¼ 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 ¼ 4.83E-10). Egyptian carcinoma also showed significantly lower frequency of nuclear b-catenin localization than the sporadic Western cancers (P ¼ 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. Cancer Epidemiol Biomarkers Prev; 21(1); 202-11. Ó2011 AACR.

Regulatory roles of microRNA-708 and microRNA-31 in proliferation, apoptosis and invasion of colorectal cancer cells

“…Previous studies have identified that there is a high frequency of methylation in the promoter of CDKN2B, leading to the downregulation of CDKN2B in colon cancer (26,27). Therefore, it was hypothesized that the low protein levels of CDKN2B in the present study may also be due to hypermethylation, however, this requires further investigation.…”

Endocrine Disruptors and Breast Cancer Risk - Time to Consider the Environment

“…Few publications attempted to dissect the relation between EDCs or other environmental toxins and breast or other cancers in Africa, Asia and South America. However, the observed Western-Eastern as well as urbanrural differences in the patterns of breast and other cancers in these geographical areas was addressed in a few studies which suggested a major role of environmental exposures (Dey et al, 2010;Nieminen et al, 2012). These data justify further studies to tackle the problem at epidemiological, clinical and molecular aspects.…”

Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma

“…While the causes for the significant differences in hypermethylation frequencies between sporadic CRCs from Finland and Australia (Table 2) are unknown, different environments [28] or population-specific features of the genetic constitution [29] could play a role. We recently described distinct epigenetic signatures of conventional TSGs for CRCs from Finland and Egypt, suggesting the possible effect of environmental exposures on colorectal carcinogenesis [30]. The selective targeting hypothesis for CIMP [31] postulates that certain regions of the genome may have intrinsic features that attract DNA methyltransferases: for example, a common polymorphism in the MLH1 promoter region (−93G > A) was shown to increase the risk of MSI colon cancer with CIMP whereas MSS-CRCs did not show this association [32].…”