A systematic review and quantitative assessment of methylation biomarkers in fecal DNA and colorectal cancer and its precursor, colorectal adenoma

Colorectal cancer (CRC) arises from accumulated genetic and epigenetic alterations, which provide the possibility to identify tumor-specific biomarkers by analyzing fecal DNA. Methylation status in human genes from tumor tissue is highlighted as promising biomarker in the early detection of CRC. A number of studies have documented altered methylation levels in DNA extracted from stool samples, but generated heterogeneous results. We performed a systematic review and quantitative assessment of existing studies to compare levels of DNA methylation in most frequently studied genes and their diagnostic value in CRC and its precursor, colorectal adenoma, with their counterparts in healthy subjects. Robust searches of the literature were performed in our study with explicit strategies and definite inclusion/exclusion criteria. Pooled data revealed that methylation levels of SFRP2, SFRP1, TFPI2, BMP3, NDRG4, SPG20, and BMP3 plus NDRG4 genes exceeded a sensitivity of 70% and a specificity of 80% for CRC detection. The DOR of the seven candidate biomarkers ranged from 19.80 to 334.33, indicating a good diagnostic power in discriminating cancer from normal tissues. The AUC range was from 0.88 to 0.95, indicating a good or very good discriminatory performance. When test results for BMP3 and NDRG4 were combined, the DOR of CRC detection was 98.36, which was higher than that for BMP3 and NDRG4 separately. As for adenoma detection, the DOR of methylated NDRG4 is higher than that for CRC (CRC vs. adenoma: 54.86 vs. 57.22). Both the sensitivity and specificity of NDRG4 for adenoma detection exceeded 70%. These findings demonstrate the eligibility and feasibility of DNA methylation as a minimally invasive biomarker in feces in the diagnosis of CRC and adenoma. The use of DNA from human stools has the potential to be readily applicable to detect aberrant DNA methylation levels among many subjects for CRC early screening.