Level of N6-Methyladenosine in Peripheral Blood RNA: A Novel Predictive Biomarker for Gastric Cancer

BACKGROUND: Dysregulation of N-6-methyladenosine (m(6)A) is associated with various human diseases including cancer. This study aimed to evaluate the level of m(6)A as a biomarker for gastric cancer (GC) diagnosis. METHODS: Peripheral blood samples were collected from 100 GC patients, 30 benign gastric disease (BGD) patients, and 75 healthy controls (HCs). Levels of m(6)A in total RNA and expression of m(6)A-related proteins were analyzed. RESULTS: The m(6)A levels in peripheral blood RNA were significantly increased in the GC group compared with those in the BGD or HC groups; moreover, levels increased with the progression and metastasis of GC and decreased in GC patients after surgery. The area under the curve (AUC) for m(6)A in the GC group was 0.929 (95% CI, 0.88-0.96), which is markedly greater than the AUCs for carcinoembryonic antigen (CEA; 0.694) and carbohydrate antigen 199 (CA199; 0.603). The combination of CEA and CA199 with m(6)A improved the AUC to 0.955 (95% CI, 0.91-0.98). The expressions of m(6)A demethylases ALKBH5 and FTO were significantly downregulated in the GC group compared with the HC group. Coculture with GC cells increased the m(6)A of RNA in promyelocytic (HL-60) and monocytic (THP-1) leukemia cells and nontumorigenic human peripheral blood B lymphocyte cells (PENG-EBV). Furthermore, a xenograft model enhanced the m(6)A in peripheral blood RNA of mice. Accordingly, expressions of ALKBH5 and FTO were decreased both in vitro and in vivo. CONCLUSIONS: Level of m(6)A in peripheral blood RNA is a promising noninvasive diagnostic biomarker for GC patients.