Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

Abstract

Background: DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC. Methods: We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage. Results: Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only. Conclusion: Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.

Evaluating the Clinical Performance of a Dual-Target Stool DNA Test for Colorectal Cancer Detection

“…20 Usually, the tested results of multitarget assays are measured by the risk scores of regression models, also called probability (ie, a positive sample has a higher probability and a negative sample has a lower probability). 50,51 Therefore, the probability cutoff would be the critical parameter of a test because different cutoff values would result in ambiguous measurements for samples near the threshold. Herein, the algorithm of iColocomf was used to determine a positive measurement as either of the dual targets showed a C T value of <38 in a valid test.…”

Genome-Wide Methylation Profiling of lncRNAs Reveals a Novel Progression-Related and Prognostic Marker for Colorectal Cancer

“…For example, by conducting a series of genome-wide DNA methylation assays among 20 normal and pre-CRC samples, including 18 low-grade adenomas and 22 high-grade adenomas, Fan et al found that the methylation alterations detected in low-grade adenoma were maintained or increased in high-grade adenoma and cancer ( 25 ). Several studies on DNA methylation biomarkers tested in fecal ( 26 , 27 ) and blood ( 28 , 29 ) samples indicated the potential of epigenetic biomarkers for early CRC diagnosis. The present study showed that DLX6-AS1 hypermethylation was detectable since the NAA stage during colorectal neoplastic progression, suggesting that this epigenetic change is a candidate driver of tumor progression.…”

Performance evaluation of stool DNA methylation tests in colorectal cancer screening: a systematic review and meta‐analysis

“…Hence, either quantitative FITs or stool DNA methylation tests may be successfully used to rule in CRC in patients with positive quantitative FIT (f‐Hb > 10 μg/g). Considering the fact that the quality of currently available studies on the accuracy of stool DNA methylation tests is low [86], their clinical utility is still limited. Therefore, further improvement of the accuracy of stool DNA methylation tests and further longitudinal studies conducted in a screening setting are warranted.…”