AbstractBackgroundEffective noninvasive biomarkers of gastric cancer (GC) are critical for early detection and improvement of prognosis. We performed genome‐wide long non‐coding RNA (lncRNA) microarray analysis to identify and validate novel GC biomarkers depending on a high‐risk population cohort.MethodsLncRNA profiles were described using the Human LncRNA Microarray between GC and control plasma samples. The differential candidate lncRNAs were validated in two stages by quantitative reverse transcription polymerase chain reaction (qRT‐PCR). We further evaluated the joint effect between the GC‐associated lncRNA andHelicobacter pylori(H. pylori) infection on the risk of cardia and non‐cardia GC, respectively.ResultsDifferent lncRNA expression profiles were identified between GC and control plasma with a total of 1206 differential lncRNAs including 470 upregulated and 736 downregulated in GC compared with the control group. The eight significantly upregulated lncRNAs (RP11‐521D12.1,AC011995.3,RP11‐5P4.3,RP11‐244 K5.6,RP11‐422 J15.1,CTD‐2306 M5.1,CTC‐428G20.2, andAC009133.20) in GC cases both in the present study and a similar microarray screening study by our collaborative team were selected for a two‐stage validation. After the large sample size validation, the subjects with higher expression ofRP11‐244 K5.6showed a significantly increased risk of GC with an adjusted odds ratio (OR) as 2.68 and 95% confidence interval (CI) as 1.15–6.24. Joint effects betweenRP11‐244 K5.6expression andH. pyloriinfection on the risk of GC were evaluated with no statistical significance.ConclusionsOur study found different lncRNA expression profiles between GC and control plasma and preliminarily identifiedRP11‐244 K5.6as a potential noninvasive biomarker for GC screening.