Abstract
BackgroundThe presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas.MethodsCandidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel.ResultsPromoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa.ConclusionsThe novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.
Highlights
The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma
Identification of the most suitable biomarkers In the evaluated 20 colon cancer cell lines, all but one (UBE3A) gene promoters were hypermethylated with frequencies ranging from 20% (LEF1 and MEF2C) to 100% (CNRIP1; Figure 1, and Additional file 2, Figure S1)
Methylation in colorectal cancers ranged from 55% (C3orf14) to 96% (BEX1; median 84%), while methylation in normal tissue was between 0% (CNRIP1, FBN1, INA) and 45% (BEX1; median 5%), P < 0.0001 to P < 0.02
Summary
The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. Most cases of colorectal cancer develop from benign precursors (adenomas) during a long time interval. This provides a good opportunity for detection of colorectal cancer at an early curable stage and to screen for potentially pre-malignant adenomas [2]. Both flexible sigmoidoscopy and the Fecal Occult Blood Test (FOBT) have been tested in randomized trials and shown to reduce mortality from colorectal cancer [3]. Only markers which provide a high methylation frequency in samples from colorectal cancer patients and at the same time lack hypermethylation in normal mucosa are suitable for a screening test
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