Bacteria-Derived Extracellular Vesicles in Urine as a Novel Biomarker for Gastric Cancer: Integration of Liquid Biopsy and Metagenome Analysis

Abstract

Early detection is crucial for improving the prognosis of gastric cancer, but there are no non-invasive markers for the early diagnosis of gastric cancer in real clinical settings. Recently, bacteria-derived extracellular vesicles (EVs) emerged as new biomarker resources. We aimed to evaluate the microbial composition in gastric cancer using bacteria-derived EVs and to build a diagnostic prediction model for gastric cancer with the metagenome data. Stool, urine, and serum samples were prospectively collected from 453 subjects (gastric cancer, 181; control, 272). EV portions were extracted from the samples for metagenome analysis. Differences in microbial diversity and composition were analyzed with 16S rRNA gene profiling, using the next-generation sequencing method. Biomarkers were selected using logistic regression models based on relative abundances at the genus level. The microbial composition of healthy groups and gastric cancer patient groups was significantly different in all sample types. The compositional differences of various bacteria, based on relative abundances, were identified at the genus level. Among the diagnostic prediction models for gastric cancer, the urine-based model showed the highest performance when compared to that of stool or serum. We suggest that bacteria-derived EVs in urine can be used as novel metagenomic markers for the non-invasive diagnosis of gastric cancer by integrating the liquid biopsy method and metagenome analysis.

Urine biomarkers in cancer detection: A systematic review of preanalytical parameters and applied methods

“…Proteins and metabolites have been investigated for their diagnostic potential for gastric cancer 132‐135 . Moreover, the microbiome and bacterial‐derived EVs have been investigated in stool, urine and serum samples to demonstrate their potential 136 …”

Gastric cancer detection by non‐blood‐based liquid biopsies: A systematic review looking into the last decade of research

“…Urine was the second most explored liquid biopsy in GC detection over the last decade, with 29 eligible studies included in this systematic review. Similarly to that observed with saliva and stool, most studies were performed in Asian populations: 12 from China, 39–50 five from Japan, 51–55 four from Taiwan, 56–59 three from South Korea, 37,60,61 and one from Iran 62 . The remaining four studies were carried‐out in Canada, 63 European portion of Russia 64,65 and Zambia 66 .…”

“…systematic review. Similarly to that observed with saliva and stool, most studies were performed in Asian populations: 12 from China, [39][40][41][42][43][44][45][46][47][48][49][50] five from Japan, [51][52][53][54][55] four from Taiwan, [56][57][58][59] three from South Korea, 37,60,61 and one from Iran. 62 The remaining four studies were carried-out in Canada, 63 European portion of Russia 64,65 and Zambia.…”

A new horizon of precision medicine: combination of the microbiome and extracellular vesicles

“…Several 16S rDNA amplicon studies using serum, urine, feces, and skin-fluid samples have shown significant differences in MEV composition between healthy and patient groups (Table 2 ). The clinical performance of the diagnostic models as evaluated by area under the curve (AUC) analysis using external validation set was 0.97, 1.00, 0.95, 0.93, 0.87, 0.82, 1.00, and 1.00 for asthma 88 , AD 89 , colorectal cancer 90 , BT 82 , hepatocellular carcinoma 91 , gastric cancer 92 , pancreatic cancer 93 , and biliary tract cancer 94 , respectively. Furthermore, diagnostic models were developed to predict the prognosis of hepatic diseases 91 .…”