Abstract
In order to assess whether N-Myc downstream regulated gene 4 (NDRG4) methylation was associated with the diagnosis and prognosis of gastric cancer, we measured the methylation of NDRG4 promoter and gene body regions among 110 gastric cancer patients using quantitative methods (MethyLight and pyrosequencing). Both NDRG4 promoter and gene body methylation levels were increased in tumor tissues than paired adjacent normal tissues (P < 0.001). NDRG4 gene body methylation was found to be significantly associated with age and tumor differentiation. NDRG4 promoter hypermethylation was proved to be a predictor of poor overall survival. However, opposite result was observed among The Cancer Genome Atlas (TCGA) cohort. The findings from gastric cell lines and public databases have suggested that NDRG4 methylation level was inversely associated with NDRG4 transcription level. Subsequent luciferase reporter gene assay showed that promoter CpG island but not gene body CpG island was able to upregulate gene expression. Collectively, NDRG4 promoter hypermethylation contributed to the risk of gastric cancer and predicted a poor prognosis in Chinese gastric cancer patients. Moreover, the combined methylation levels of NDRG4 promoter and gene body served as diagnostic biomarkers in gastric cancer.
Highlights
Gastric cancer is the third leading cause of cancerrelated mortality and the fourth most prevalent cancer in the world [1]
N-Myc downstream regulated gene 4 (NDRG4) acts as a candidate tumor suppressor gene whose expression is frequently repressed by its promoter methylation in colorectal cancer
Previous study has showed that the poor outcome of patients with glioblastoma was associated with NDRG2 methylation and reduced expression [22]
Summary
Gastric cancer is the third leading cause of cancerrelated mortality and the fourth most prevalent cancer in the world [1]. In China, gastric cancer is the second commonly diagnosed cancer, accounting for 679,100 novel cases and 498,000 cancer-associated mortalities from 2009 to 2011 [2]. The incidence of gastric cancer has a male : female ratio of approximately 2:1 [2]. The majority (about 90%) of gastric cancer belongs to the pathological subtype of adenocarcinoma [3]. Surgical resection remains the primary treatment for gastric cancer; the five-year survival rate for late stage gastric cancer rarely exceeds 5% [4, 5]. Tumor node metastasis (TNM) staging classification is the most common tool in the prediction of gastric cancer prognosis. The latest edition of the TNM classification couldn’t satisfy the www.impactjournals.com/oncotarget
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