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DOI: 10.1101/2023.05.24.542159

Validation of hypermethylated DNA regions found in colorectal cancers as potential aging-independent biomarkers of precancerous colorectal lesions

S.Sajibu E. Sonder A. Tiwari ...+5 M. D. Robinson
摘要
Background: We previously identified 16,772 colorectal cancer-associated hypermethylated DNA regions that were also detectable in precancerous colorectal lesions (preCRCs) and unrelated to normal mucosal aging. We have now conducted a study to validate 990 of these differently methylated DNA regions in a new series of preCRCs. Methods: We used targeted bisulfite sequencing to validate these 990 potential biomarkers in 59 preCRC tissue samples (41 conventional adenomas, 18 sessile serrated lesions), each with a patient-matched normal mucosal sample. Differential DNA methylation tests for each CpG dinucleotide were conducted, with results aggregated at region level, to choose panels of candidate biomarkers that were (cross-)validated with respect to their stratifying potential between preCRCs and normal mucosas as well as on an independent cohort. Results: Strong differences in methylation level were observed across the full set of 990 investigated DMRs. Among the 100 randomly selected panels of 30 DMRs analyzed with our bioinformatic approach, the best performing panel correctly classified 58/59 tumors (area under the receiver operating curve: 0.998). Conclusions: These validated DNA hypermethylation markers can be exploited to develop more accurate noninvasive colorectal tumor screening assays.
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