SDC2 and TFPI2 Methylation in Stool Samples as an Integrated Biomarker for Early Detection of Colorectal Cancer

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.

RETRACTED: Using Comorbidity Pattern Analysis to Detect Reliable Methylated Genes in Colorectal Cancer Verified by Stool DNA Test

“…Methylated SDC2 is known as a valuable biomarker for CRC detection. The sensitivity and specificity by methylated SDC2 for CRC detection in three commercial methylation kits, IColocomf (Ammunition Life Technology Co., Ltd., Wuhan, China), Colosafe (Creative Biosciences CO., Ltd., Guangdong, China), and COLOWELL (RealBio Technology CO., Ltd., Shanghai, China) were 77% and 98%, 84% and 98%, and 71% and 94%, respectively [28,31,32]. Although methylated SDC2 had a lower sensitivity for CRC screening in the present study than that reported previously, the sensitivity and specificity of the three gene combination for CRC detection were comparable to those results previously (Table 2).…”

A novel method for early detection of colorectal cancer based on detection of methylation of two fragments of syndecan-2 (SDC2) in stool DNA

“…It has been widely accepted that age is a high‐risk factor for genome DNA methylation, and many tumor suppressor genes have been reported to be age‐dependent hypermethylated genes. However, the methylation of SDC2 did not show a strong correlation with age in our study and previous studies [ 29 , 30 , 34 ]. Our study and previous publications demonstrated that SDC2 methylation is independent of patients’ clinical features, including sex, age, the location of the tumors and clinical stage.…”

Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review

“…Combined mSDC2 and mTFPI2 measurements showed a higher sensitivity for identifying adenoma and CRC. Moreover, methylation determination in stool probes outperformed FOBT and protein markers [ 64 ]. When a panel containing mSDC2, methylated secreted frizzled-related protein 1 (mSFRP1), methylated secreted frizzled-related protein 2 (mSFRP2) and methylated proline-rich membrane anchor 1 (mPRIMA1) was investigated for detecting adenoma and CRC in plasma, a higher performance was obtained compared with each methylated gene alone [ 65 ].…”