https://orcid.org/0000-0002-2566-7843
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Abstract
Background
Detection of aberrant methylated DNA in the stool is an effective early screening method for colorectal cancer (CRC). Previously, reporters identified that syndecan-2 (SDC2) and tissue factor pathway inhibitor 2 (TFPI2) were aberrantly methylated in most CRC tissues. However, the combined diagnostic role of them remains undefined. Our research aimed at probing the role and efficiency of the methylation status of SDC2 and TFPI2 in CRC early screening by using bioinformatics analysis and clinical stool sample validation.
Methods
The promoter and CpG site methylation levels of SDC2 and TFPI2 and their correlation with clinicopathological characteristics of CRC were analyzed using UALCAN, Methsurv, and Wanderer. UCSC Xena was used to perform survival analyses. LinkedOmics was used to do functional network analysis. DNA was isolated and purified from stool, and quantitative methylation-specific PCR (qMSP) was applied to detect methylatedSDC2 and TFPI2.
Results
The results showed that promoter and most CpG site methylation levels of SDC2 and TFPI2 were significantly higher in CRC than in normal tissues. Moreover, SDC2 and TFPI2 methylation showed a positive correlation. Functional network analysis suggested that both methylated SDC2 and TFPI2 were involved in tumor cells’ metabolic programs. Besides, there was a higher positive integrated detection rate in CRC (n=61) with a sensitivity of 93.4% and in adenoma (Ade) (n=16) with a sensitivity of 81.3% than normal with a specificity of 94.3% in stool samples. What is more, integration of methylated SDC2 and TFPI2 showed a higher sensitivity and Youden index than a single gene in detecting Adeor CRC.
Conclusion
Our data indicate that SDC2 and TFPI2 were hypermethylated in CRC, and integrated detection of methylated SDC2 and TFPI2 in stool has the potential to be an effective and noninvasive tool of CRC early screening.
Acknowledgments
This study was supported by grants from National Natural Science Foundation of China (81872376), National Natural Science Fund Youth Fund of China (81702411), and Health Commission of Hubei Province Scientific Research Project (WJ2019H012). We would like to acknowledge the staffs at Wuhan Ammunition Life-tech Co. Ltd for their technical assistance.
Abbreviations
SDC2, syndecan-2; TFPI2, tissue factor pathway inhibitor 2; CRC, colorectal cancer; Ade, adenoma; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; FOBT, blood testing; FIT, fecal immunochemical test; GSEA, gene set enrichment analysis; GC, gastric cancer.
Data Sharing Statement
All data generated in this study can be obtained by contacting the corresponding author.
Ethics Approval and Consent to Participate
This study was approved by the Ethics Committee of Medicine of Wuhan University, and written informed consent was obtained from all study participants. Sample collection was conducted in accordance with the Declaration of Helsinki.
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflicts of interest in this work.