The Methylation of SDC2 and TFPI2 Defined Three Methylator Phenotypes of Colorectal Cancer

Abstract BackgroudMethylated SDC2 and TFPI2 are applied frequently for the early detection of colorectal cancer (CRC). However, they often miss some positive samples, which directly affects their sensitivities, and the underlining mechanism is not well known.Methods:CRC samples from TCGA and GEO datasets were divided into three groups, Highmethylation/ High-methylation (HH), High-methylation/Low-methylation (HL), and Lowmethylation/Low-methylation (LL) according to the methylation status of SDC2 and TFPI2 promoters. Variations in age, tumor location, and microsatellite instable were then assessed between the three groups and verified in our custom cohort.ResultsSamples of HL group preferred to derive from left-sided CRCs (P < 0.05). HH samples showed the highest microsatellite instability and mutation load (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02, P = 0.0055). Almost all mutations of BRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were observed in HH group (HH/HL/LL: 51/0/1, P = 0.018). Besides, older patients were frequently found in HH group. Expression analysis identified 37, 84, and 22 group-specific differentially expressed genes (DEGs) for HH, HL, and LL, respectively. Functional enrichment analysis revealed that HH-specific DEGs were mainly related to transcription regulation, while LL-specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration.Conclusions:The three methylation phenotypes identified based on SDC2 and TFPI2 methylation status showed extensive variations in tumor location, patient age, MSI and ECM biology processes, suggesting that these respective sides should be considered when developing new methylation-based biomarkers for CRC detection.