A panel of DNA methylated markers predicts metastasis of pN 0 M 0 gastric carcinoma: a prospective cohort study

The aim of this prospective study was to evaluate the feasibility of predicting GC metastasis using CDH1, GFRA1, P16 and ZNF382 DNA methylation as biomarkers. 198 GC patients without metastasis at the time of surgery resection were recruited into the double-blind cohort (NCT02159339). Gene methylation was analysed using MethyLight assays. GC metastasis and survival data were obtained from 178 patients with 94.7% compliance during follow-up. Twenty six cases of metastasis and 5 cases of recurrence were observed in 178 cases (17.4%) during the follow-up (median, 62.7 months). The GC metastasis rate for GFRA1 methylation-positive patients was significantly reduced compared with GFRA1 methylation-negative patients (odds ratio [OR]: 0.23, 95% confidence interval [CI] 0.08–0.66). Similar results were also observed using ZNF382 methylation as a predictor (OR: 0.17, 95% CI 0.06–0.47). A risk score including methylation of GFRA1 and ZNF382 was generated. The metastasis rate was significantly increased in high-risk GC patients (OR: 4.71, 95% CI: 1.85–12.00). GC patients with high risk had a shorter overall survival, especially for patients with stage I GC (P = 0.024). The combination of GFRA1 and ZNF382 methylation is a biomarker panel for the prediction of GC metastasis.