Liquid biopsy in gastric cancer: predictive and prognostic biomarkers

Abstract

Gastric cancer (GC) is a high-incidence cancer worldwide. Most patients are diagnosed at an advanced stage, by which time they have limited treatment options and poor prognosis. Early diagnosis and precise treatment are important. In the past few years, emerging research has been conducted on the use of non-invasive liquid biopsy, with its advantages of minimal invasiveness and repeated sampling, to monitor tumor occurrence and recurrence in real time and to evaluate prognosis and treatment response. Many studies have demonstrated the potential of liquid biopsy in GC, and the detection of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating free DNA (cfDNA), and exosomes has achieved gratifying results. In this review, we summarize evolving technologies for and information regarding liquid biopsy, the most recently discovered GC liquid biopsy biomarkers, and ongoing clinical trials and discuss the challenges and application prospects of liquid biopsy in GC.

Fig. 1. Flowchart of applying liquid biopsy in GC.

Blood, saliva, urine, and gastric juice are collected and targets of liquid biopsies, such as CTCs, ctDNA/cfDNA or exosome RNAs, were enriched to achieve early detection, prognosis, and monitoring therapy responses.

Fig. 2. Components of liquid biopsy in GC.

CTCs, ctDNA, and exosomes were discovered in the peripheral blood. CTCs and ctDNA are important ingredients that are usually regarded as the foundations of liquid biopsy. ctDNA is formed from apoptotic and necrotic tumor cells, which release fragmented DNA into the bloodstream and possess genetic aberration from original tumor cells. CTCs are cancer cells that spontaneously shed from primary or metastatic tumors and circulate in the circulation. They are tumor “seeds” and can result in recurrence by hepatic metastasis, lymphatic metastasis, and angiogenesis.

Fig. 3. Network and timing analysis based on published literature.

Articles published on the Web of Science in the past five years were retrieved and results were visualized through bibliometric methods by VOSviewer and CiteSpace. “Gastric cancer” and “Liquid biopsy” are set as keywords to draw the network and time series diagrams to analyze the development trends in this field. Each node represents different research content. The size of each node indicates the frequency of occurrence, the thickness of the connection between the nodes indicates the strength of the association, and the different color represent the temporal characteristics of the nodes.

Fig. 4. Overview of characteristics and clinical applications of liquid biopsy in gastric cancer.

Liquid biopsy is regarded as an important tool in the future, as it could achieve multiple goals, such as early detection, medication guidance, treatment monitoring, resistance testing, minimal residual disease (MRD) detection, survival analysis and metastatic prediction. CTCs and ctDNA/cfDNA are primary targets of liquid biopsy, while other targets are being explored, for example, exosomes containing proteins or DNA and RNA fragments, tumor-educated platelets and circulating tumor proteins. Methods like mutation profiling, CNA profiling, methylation profiling and preferred end coordinates detections are used to acquire qualitative and quantitative information of ctDNA. Assays for single locus and multiple target gene panel are being developed. CTCs provide DNA, RNA protein expression and molecular phenotype at single cell level and can be cultured in vivo or in vitro for further investigation.