Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality in the United States and China, there is an urgent need to discover novel non-invasive biomarkers for the early diagnosis of GC to improve the prognosis of GC patients. Exosomal miRNAs are considered promising biomarkers for cancer diagnosis. Using next-generation sequencing (NGS), bioinformatics and further validation, we identified and evaluated exosomal miRNAs in serum as early diagnostic markers for GC. NGS revealed that the average mappable reads in the RNA libraries were about 6.5 million per patient including miRNAs (73.38%), rRNAs (17.10%), snRNAs (8.83%), snoRNAs (0.65%), and tRNAs (0.04%). A total of 66 up and 13 down-regulated exosomal miRNAs were found in the screened cohort. In the validation cohort, by comparing with healthy individuals, higher levels of serum exosomal miR-92b-3p, let-7g-5p, miR-146b-5p, and miR-9-5p were found to be significantly associated with early-stage GC (p < 0.05). Diagnostic power of the combined panels of the exosomal miRNAs or the combination of exosomal miRNAs and CEA outperformed that of single exosomal miRNA marker for establishing a diagnosis of early-stage GC. The combined diagnosis of exosomal miR-92b-3p + let-7g-5p + miR-146b-5p + miR-9-5p with CEA had the most powerful efficiency with an AUC up to 0.786. In addition, serum levels of exosomal miR-92b-3p were significantly associated with poor cohesiveness (p = 0.0021), let-7g-5p and miR-146b-5p were significantly correlated with nerve infiltration (p = 0.0234 and p = 0.0126, respectively), and miR146b-5p was statistically correlated with tumor invasion depth in early-stage GC (p = 0.0089). In conclusion, serum exosomal miR-92b-3p, -146b-5p, -9-5p, and let-7g-5p may serve as potential non-invasive biomarkers for early diagnosis of GC.
Highlights
Gastric cancer (GC) remains a leading cause of cancer-related mortality in the United States (Bray et al, 2018) and China (Chen et al, 2018)
Exosomes act as mediators in intercellular communications by transporting proteins, lipids and nucleic acids to recipient cells, resulting in the modulation of different processes such as tumor invasion, angiogenesis, metastasis, and chemoresistance (Kosaka et al, 2016; Hu et al, 2019)
Gender, pathological differentiation, pathological tumor stage, tumor invasion depth, presence of lymph node metastases, WHO cohesiveness, carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) levels, and nerve infiltration were collected from medical records
Summary
Gastric cancer (GC) remains a leading cause of cancer-related mortality in the United States (Bray et al, 2018) and China (Chen et al, 2018). Because GC is mostly asymptomatic until it progresses to advanced stages, and lacking of an efficient biomarker with high sensitivity and specificity, the prognosis of GC patients remains poor. There is an urgent need to discover novel non-invasive biomarkers for the early diagnosis of GC. High stability and enrichment of circulating exosomal miRNAs offer an attractive option for cancer diagnosis and prognosis. Serum exosomal miR-1246 and miR21 could be used as promising diagnostic biomarkers for pancreatic cancer (Madhavan et al, 2015; Lai et al, 2017), prostate cancer (Bhagirath et al, 2018), and hepatocellular carcinoma (Sugimachi et al, 2015). The relevance of serum exosomal miRNAs in early-stage GC has not been clearly elucidated
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