Zic1 Promoter Hypermethylation in Plasma DNA Is a Potential Biomarker for Gastric Cancer and Intraepithelial Neoplasia

Gastric cancer (GC) remains one of the most common digestive cancers worldwide; however, most patients present at an advanced stage at initial diagnosis. Zic1 is a novel candidate tumor suppressor gene that is epigenetically silenced in GC. In this study, we investigated Zic1 promoter methylation in plasma DNA as a novel molecular marker for the early diagnosis and monitoring of GC. Methylation-specific polymerase chain reaction (MSP) assay was performed to detect Zic1 promoter methylation in plasma DNA from 20 healthy subjects, 50 gastric intraepithelial neoplasia patients, and 104 GC patients. The Zic1 promoter methylation rate in the plasma samples from the healthy control group was 0%, but it reached 54.0% in the intraepithelial neoplasia group and 60.6% in the GC group. The latter two values were significantly higher than that found in the healthy control group (p < 0.05), with a 100% specificity for intraepithelial neoplasia and GC diagnosis. The positive predictive value of plasma Zic1 promoter methylation for the diagnosis of intraepithelial neoplasia and GC was 100%. Methylation status in the GC group was not significantly associated with tumor size, tumor differentiation, lymph node metastasis, TNM staging, or tumor invasion (p > 0.05). Assessment of the significance of detection of the carcino-embryonic antigen (CEA) level and Zic1 promoter methylation rate for GC diagnosis revealed that the sensitivity of Zic1 promoter methylation was significantly higher than that of the CEA level as a marker and that the combined measurement of these two indices (parallel testing) improved sensitivity. Taken together, our results suggest that the Zic1 promoter methylation rate in plasma-derived DNA is of great significance for the early screening of GC and monitoring of tumorigenesis. Zic1 promoter methylation may serve as a novel non-invasive plasma biomarker for the early detection of GC and for risk assessment in high-risk populations. The combined measurement of the Zic1 promoter methylation rate and CEA level (parallel testing) may enhance the current guidelines for the early diagnosis of GC.