Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors

Abstract

Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC ¼ 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. Cancer Prev Res; 4(5); 674-83. Ó2011 AACR.

Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

“…Recently, miR-34a methylation was detected in DNA present in mucosal wash fluid from patients undergoing colonoscopy (44). Moreover, systemic delivery of miR-34a was shown to reduce tumor burden and growth of xenografts in mice and led to reduced metastasis (9,(45)(46)(47).…”

DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

“…Another remarkable example is VIM (15, 18), which is the cornerstone of ColoSureÔ, the only currently commercially or clinically available fecal DNA test marketed for CRC screening in the United States (33). Other studies have attempted to define comprehensive panels of DNA methylation biomarkers to test in stool samples, being frequently based on candidate gene approaches investigating frequent targets of aberrant hypermethylation in cancer (34). A compiler meta-analysis evaluating several studies reporting aberrantly methylated genes as biomarkers for CRC diagnosis reported an overall sensitivity and specificity of 0.54 and 0.88, respectively.…”

Epigenetically regulatedMIR941andMIR1247target gastric cancer cell growth and migration

“…37 Furthermore, the use of miRNA gene hypermethylation to improve cancer diagnosis has been extended recently to include the use of samples that can be obtained non-invasively, such as serum, 38 feces, 39 and colorectal mucosal wash fluids. 40 In terms of the therapeutic potential of miRNAs, several strategies have been proposed to restore the function of tumor suppressor miRNAs that are downregulated in cancer. 41 This reexpression may be achievable with the use of DNA demethylating agents and histone deacetylase inhibitors for epigenetically inactivated tumor suppressor miRNAs.…”