Site-Specific Hypermethylation of SST 1stExon as a Biomarker for Predicting the Risk of Gastrointestinal Tract Cancers

Abstract

Background. DNA methylation is an important epigenetic modification in tumorigenesis, and similar epigenetic regulation mechanisms have been found in the gastrointestinal tract (GIT) cancers. Somatostatin (SST) has been confirmed to be expressed throughout the GIT. This study aimed to simultaneously explore the relationships between the SST methylation and the risks of three GIT cancers (esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC)) and to evaluate its diagnostic value. Methods. Differentially methylated regions (DMRs) of the SST gene, including TSS200, 1stExon, and the gene body, were identified in GIT cancers by The Cancer Genome Atlas (TCGA) database analysis. Further analyses were conducted in tissue samples of EC ( $n=50$ ), GC ( $n=99$ ), and CRC ( $n=80$ ). The SST methylation was detected by bisulfite-sequencing PCR (BSP), and the SST expression was detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Results. In GIT cancers, DMR-related CpG islands were mainly located in the 1stExon. The methylation status of the SST 1stExon in the tumor tissues was significantly higher than that in the adjacent noncancerous tissues, and the methylation rates of the specific CpG sites were correlated with clinical phenotypes. The average methylation rate (AMR) of the SST 1stExon was negatively correlated with the SST gene expression in GC and CRC (both $P<0.001$ ). For the diagnosis of GIT cancers, the combined detection of methylation at CpG sites +18 and +129 showed the highest area under the curve (AUC 0.698), with a sensitivity of 59.3% and a specificity of 72.8%. Conclusions. The site-specific hypermethylation of the SST 1stExon increases the risk of GIT cancers and might be a potential predictive marker for pan-GIT cancers.