Abstract
Background: SDC2 methylation is a feasible biomarker for colorectal cancer detection. Its specificity for colorectal cancer is higher than 90%, but the sensitivity is normally lower than 90%. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation. Methods: Hypermethylated TFPI2 was identified in SDC2 hypomethylated colorectal cancer samples retrieved from TCGA database with the methylation level lower than 0.2. The methylation-specific PCR assay was developed and then evaluated using tissue samples (184 cancer and 54 healthy control samples) and stool samples (289 cancer, 190 adenoma, and 217 healthy control samples). Results: TFPI2 was hypermethylated in most SDC2 hypomethylated colorectal cancer samples. When the SDC2/TFPI2-combined PCR assay was performed in stool specimens, the AUC value of cancer vs. control was 0.98, with the specificity of 96.40% and sensitivity of 96.60%, and the AUC value of adenoma vs. control was 0.87, with the specificity of 95.70% and the sensitivity of 80.00%. The improvement in sensitivity was the most momentous in the left colon. As the detection index, the Ct value was better in improving the sensitivity of detection than the methylation level based on the 2−ΔΔCt value. Conclusion: TFPI2 can improve the sensitivity of SDC2 methylation–specific detection of colorectal tumorous lesions while maintaining high specificity, in particular reducing the missed detection of left colon cancer and adenoma.
Highlights
Colorectal cancer (CRC) affects millions of people around the world
The Cancer Genome Atlas (TCGA), GSE48684, and GSE79740 were used to identify and validate differential methylation regions and D184 and D289 to evaluate the performance of methylation-specific PCR (MSP) assays in clinical samples
Specimen type Data source Methoda,b Methylation indicator Normal specimens Adenoma specimens CRC specimens Demographic featurec Used in this study for Tissue GPL13534 450k β values 45 0 411 Table S4 Marker discovery
Summary
Colorectal cancer (CRC) affects millions of people around the world. It is unique because of slow progress, making it preventable and often curable (Cao et al, 2021; Sung et al, 2021). The five-year survival rate can be as high as 90% or less than 10%, depending on the stage of diagnosis (American Cancer Society, 2019). The occurrence of CRC is related to genomic and epigenetic changes, such as gene mutation, microsatellite instability, and CpG island aberrant methylation (Grady and Pritchard, 2014). CpG island methylation is the most common change (Yiu and Yiu, 2016). SDC2 methylation is a feasible biomarker for colorectal cancer detection. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation
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