A panel of DNA methylated markers predicts metastasis of pN0M0 gastric carcinoma: a prospective cohort study

Zhaojun Liu, Xiaojing Cheng, Lianhai Zhang, Jing Zhou, Dajun Deng, Jiafu Ji, Zhaojun Liu, Xiaojing Cheng, Lianhai Zhang, Jing Zhou, Dajun Deng, Jiafu Ji

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: The combination of GFRA1 and ZNF382 methylation is a biomarker panel for the prediction of GC metastasis.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Participant flow diagram
Fig. 2
Fig. 2
Comparison of the proportions of methylated-gene alleles in gastric carcinoma (GC) and corresponding surgical margin (SM) samples from 151 GC patients using MethyLight analysis. a CDH1; b GFRA1; c P16; d ZNF382
Fig. 3
Fig. 3
ROC curves for the prediction of GC metastasis by GFRA1, ZNF382, CDH1 and P16 methylation positivity as biomarkers. The cut-off value to define methylation-positive patients is noted. a GFRA1; b ZNF382; c CDH1; d P16
Fig. 4
Fig. 4
Kaplan–Meier survival curves of gastric carcinoma (GC) patients with different GFRA1/ZNF382 methylation states and numbers of risk factors in GC tissues. a, c, e Relapse-free survival (RFS); (b, d, f) Overall survival (OS)

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