Bibliometric analysis of global research on liquid biopsy for gastric cancer.

Introduction
Gastric cancer (GC) remains a significant global health challenge, ranking as the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide [1]. Owing to its often advanced stage upon diagnosis, the mortality rate of GC is high [2]. It is estimated that approximately 769,000 people died of GC worldwide in 2020 [1]. In Eastern Europe, East Asia, and South America, there are areas with relatively high incidence and mortality rates of GC [2]. The incidence of GC is twice as high in males as in females [1]. Currently, for patients with GC, endoscopy, surgical resection, and systemic chemotherapy are the primary treatment methods [2, 3]. However, although molecular targeted therapy and immunotherapy are increasingly being applied to some patients, the overall survival rate remains poor [3, 4]. The early detection of GC is crucial for its treatment and prognosis [5]. The diagnosis of GC primarily relies on imaging and pathological biopsy [6]. Nevertheless, imaging is unable to provide real - time tumor monitoring and exposes patients to radiation [7]. Therefore, a reliable tool is urgently needed to enable early detection, track disease recurrence, and precisely forecast prognosis or therapeutic response in patients with GC.
Liquid biopsy (LB) is a non-invasive diagnostic method that analyzes biomarkers in bodily fluids (typically blood, urine, bile, cerebrospinal fluid) to detect and monitor diseases like cancer [8, 9]. By examining tumor-derived components such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-educated platelets, tumor-derived extracellular vesicles (EVs), exosomesand, circulating cell-free RNA (cfRNA), it identifies cancer markers including molecular alterations, cancer cells, and metabolic byproducts [10, 11]. This innovative technique enables real-time tumor monitoring, early recurrence detection, and personalized treatment planning-offering a minimally invasive alternative to tissue biopsies [9]. Despite its numerous advantages, there are also some limitations in its analysis, such as low sensitivity. In recent years, numerous articles have summarized the role of liquid biopsy in multiple cancers, including breast cancer [12], ovarian cancer [13], hepatocellular carcinoma [14], non-small cell lung cancer [15], and colorectal cancer [16]. Currently, the US FDA has approved five LB companion diagnostic assays for clinical use in these cancers: breast cancer, non-small-cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer, and solid tumors [9, 17]. Although the research on LB associated with gastric GC remains in its nascent stage, the quantity and quality of related research have increased recently.
Bibliometric analysis, introduced by Pritchard in 1969, is a well-known statistical method that has been widely applied in the medical field recently [18]. This method offers an overview of a field’s development, identifies key areas and emerging trends, and guides future research [19]. Unlike traditional systematic reviews, bibliometric analysis helps new or cross-disciplinary researchers quickly grasp a field’s development and current state via thematic clustering, avoiding extensive literature review [20]. Previous bibliometric analyses have reported the hotspots and frontiers of LB in multiple cancers [8, 13]. As far as we know, a bibliometric analysis of LB in GC has not been published. In this bibliometric study, we quantitatively reviewed and visualized the advancements in LB as a diagnostic tool for GC over the past twenty-five years, highlighting its potential in early detection and the types of biomarkers utilized. Our focus was on identifying crucial research trends, well - known teams, leading research institutions and notable advancements in the field.

Materials and methods

Data source and search strategy
The Web of Science Core Collection (WOSCC), an internationally recognized, multidisciplinary citation index and the most authoritative tool for scientific literature, provides comprehensive bibliographic data for bibliometric analysis [21]. Therefore, WOSCC acts as the main data source for analysis in this study. The information was extracted using the following search criteria: (TS = “gastric cancer” OR “gastric tumor” OR “stomach tumor” OR “stomach cancer” OR “gastric neoplasm” OR “stomach neoplasm”) AND (TS = “liquid biopsy”). The search was limited to publications between January 1, 2000 and August 31, 2025, and only English - language publications were included. Document types included articles and reviews but excluded other types such as editorials, early accesses, letters, proceeding papers, corrections, retracted publications, and meeting abstracts. Two researchers independently conducted the literature retrieval and screening. Any discrepancies are resolved by consultation with a third researcher.

Data analysis
CiteSpace, developed by Professor Chaomei Chen, is a Java-based bibliometric software [22]. It applies co-citation analysis and pathfinder network algorithms to scientific literature, generating visual knowledge maps that reveal a field’s research evolution, hotspots, and frontiers [23]. In this study, the screened records were exported in plain text format, including full records and cited references. Bibliometric analysis and all data visualizations were conducted using Excel 2021, VOSviewer (version 1.6.18) and CiteSpace (version 6.3.1). Specifically, Excel 2021 was used to create general descriptive charts of the publications, while VOSviewer and CiteSpace were employed to perform visual analyses.

Results

Annual publication trend
According to the search strategy, a total of 360 publications related to LB in GC were identified, including 228 original articles and 132 reviews. A flowchart of data retrieval and literature screening of our study is illustrated in Fig. 1. As shown in Fig. 2, the number of publications in this field has exhibited a steady upward trend from 2002 to 2025. Notably, there was a significant increase in research output and advancements in GC treatment beginning around 2016. This surge suggests a heightened interest and recognition among scholars in the clinical significance and research significance of LB technologies in GC.

Author analysis
A total of 2822 authors contributed to the 360 publications retrieved. According to Price’s Law, the number of core authors (N) is calculated using the formula: N = 0.749 × (ηmax)1/2, where ηmax represents the number of publications by the most prolific author. With ηmax = 8, the value of N is calculated to be 2.12, which means that authors who have published more than 3 articles are considered core authors in this field. Based on analysis with VOSviewer, a total of 72 core authors were identified, who collectively published 286 articles, accounting for 79.4% of the total publications. This indicates that a relatively small group of researchers has made a major contribution to the development of this field. Table 1 presents the top 11 most productive authors, among whom Ichikawa D stands out as the most prolific, with 8 publications and 338 citations, highlighting his significant academic influence in this field. As shown in Fig.3, the co-authorship network reveals multiple closely connected clusters, indicating collaborative communities among active researchers. The network reveals several cohesive research communities, notably those centered around Zhao Qun, Shen Lin, Goel Ajay, and Konishi Hirotaka, which demonstrate high intra-group connectivity and intensive collaborative activity. The dense interconnections within clusters and sparser links between them suggest the presence of well-defined academic subgroups, while a few bridging authors facilitate cross-group collaboration. This structure highlights both the central contributors and the fragmented yet evolving nature of scholarly cooperation in this domain.

Country and institution analysis
As shown in Table 2, China emerges as the most productive country, contributing 146 publications, followed by the USA (78) and Japan (51). These three countries together account for a substantial proportion of the total research output in this field. In total citations, China leads with 3985, closely followed by the USA (2297) and Japan (1708). Notably, the UK exhibits the highest average citation per publication (40.8), suggesting that despite its lower publication count (21 publications), the research conducted has yielded highly impactful and quality outcomes. Similarly, Japan also demonstrates a robust citation performance, with an average of 33.5 citations per article, as highlighted in recent reports. This reflects its significant academic influence.
The international collaboration network (Fig.4) illustrates the global landscape of research on LB in GC. The map reveals several regional clusters and highlights key countries that play central roles in international cooperation. Notably, China and the USA emerge as the most productive and collaborative countries, occupying central positions with the highest link densities, suggesting their leading roles in driving global research. Japan, South Korea, and Germany also show strong collaboration ties with both China and the USA, forming a densely connected triad of academic exchange. Additionally, countries such as Italy, the UK, and Australia contribute significantly and act as key bridges within their respective clusters. Meanwhile, a cluster including Morocco, Ethiopia, and Kenya represents a group of emerging contributors with increasing participation in recent years. This pattern highlights a core-periphery structure, where a few countries dominate global research and collaboration, while others are gradually integrating into the international academic community, fostering a more globalized research landscape.

As shown in Table 3, Peking University ranks first with 13 publications, receiving a total of 688 citations, and achieves the highest average citation per article (52.9), highlighting its prominent academic influence and high-impact output. Other leading institutions include Chinese Academy of Sciences (11 publications), Fudan University (10 publications), and Shanghai Jiao Tong University (9 publications). These institutions, meanwhile, make substantial contributions to the total publication volume; their average citations per publication vary, ranging from 7.8 to 50.3. These results suggest that Chinese institutions are highly productive. In contrast, Korean and American institutions such as Sungkyunkwan University and Mayo Clinic show stronger citation performance, which indicates greater international visibility and academic impact.

The institutional collaboration network (Fig.5) provides a visual representation of the cooperative landscape among research organizations, showcasing the intricate relationships and collaborative trends within the field. The network reveals several prominent clusters, reflecting both regional consolidation and international cooperation. Chinese institutions dominate the central structure of the map, with Fudan University, Peking University, Shanghai Jiao Tong University, and the Chinese Academy of Sciences serving as key hubs. These institutions form a tightly interlinked cluster, indicating a high level of domestic collaboration and institutional synergy. Another densely connected cluster is centered around Hebei Medical University, Nanjing University, and Nanjing University of Chinese Medicine, suggesting strong regional research integration within Jiangsu and Hebei provinces. On the international front, organizations such as Mayo Clinic, Beckman Research Institute, and Sungkyunkwan University are embedded within transnational clusters, highlighting active cross-border research partnerships, particularly between East Asia and North America.

Journal citation and co-citation analysis
To identify the core publication sources and foundational knowledge base of LB for GC, both journal citation and co-citation analyses were conducted. As shown in Table 4; Fig. 6a, ‘Cancers’, ‘Frontiers in Oncology’, and ‘World Journal of Gastroenterology’ are the most prolific journals, occupying central positions in the network, indicating their pivotal role in disseminating research on LB for GC. While ‘Cancers’ ranks first in output (27 documents), ‘Molecular Cancer’ stands out for its exceptionally high citation count (541) and impact factor (IF = 33.9), despite fewer publications, indicating strong academic influence and recognition. The density and proximity of nodes in the network reflect the strength of co-publishing relationships, suggesting that the research in this field is highly interdisciplinary, spanning oncology, molecular biology, and gastroenterology. Multiple tightly clustered groups represent specialized journal communities, which may imply thematic research directions or collaborative publishing trends.
As shown in Table 5; Fig. 6b, ‘Clinical Cancer Research’ and ‘Journal of Clinical Oncology’ emerge as the most frequently co-cited journals, suggesting their pivotal role in shaping the theoretical and empirical framework of the field. High-impact general science journals such as ‘Nature’ (IF = 48.5) and ‘Annals of Oncology’ (IF = 65.4) also feature prominently, reflecting the interdisciplinary and translational nature of current research. The presence of clusters with distinct colors indicates several thematic subfields, including clinical oncology, translational research, and molecular mechanisms of cancer. The size of each node is proportional to its total link strength, with larger nodes representing journals that are more frequently cited together. This implies that these journals provide a theoretical and methodological backbone for current research endeavors.

Keyword analysis
To elucidate the research hotspots and evolving trends in LB for GC, a comprehensive keyword co-occurrence analysis was conducted using VOSviewer, as shown in Fig. 7; Table 6. Figure 7a illustrates the co-occurrence network of keywords, revealing the primary research themes and conceptual relationships in LB for GC. The network comprises several distinct clusters, each representing a thematic concentration. The most frequently occurring keywords include “liquid biopsy,” “gastric cancer,” “biomarker,” “ctDNA,” “cfDNA,” “exosome,” and “circulating tumor cell”, which occupy central positions in the network, indicating their fundamental roles in the research domain. The dense interconnections among these terms suggest that biomarker discovery, tumor-derived nucleic acids, and circulating tumor components are core topics underpinning the current research landscape. Figure 7b presents the temporal evolution of keyword usage based on the average publication year. Keywords such as “liquid biopsy,” “gastric cancer,” and “ctDNA” appear in green and blue, indicating they have remained central throughout the study period. In contrast, emerging terms such as “exosome,” “immunotherapy,” “cfDNA,” “open-label,” and “helicobacter pylori” appear in yellow, suggesting their recent rise in scholarly attention. This shift highlights a growing interest in integrating liquid biopsy with novel therapeutic strategies and exploring its application in early diagnosis, prognosis, and treatment monitoring of gastric cancer.
Citation burst analysis identifies keywords that have received a sudden surge in attention over a specific period, highlighting emerging research frontiers and evolving academic interests. As shown in Fig. 8, keywords such as “peripheral blood”, “plasma DNA”, and “prognostic value” exhibit the strongest citation bursts around 2017–2019, reflecting early interest in non-invasive biomarkers. More recently, “serum” and “marker” have shown ongoing bursts (2021–2025, 2023–2025), indicating a current research focus on practical diagnostic tools. These bursts highlight the evolving attention from molecular exploration to clinical application in LB for GC.

Cited reference analysis
The cited reference analysis visualized in Fig.9 reveals the core literature that has profoundly shaped research on LB in GC. As shown in the co-citation network (Fig.9a), three major clusters emerge: epidemiological studies (red), molecular mechanisms and biomarker discovery (green), and technical or methodological innovations (blue). Central references with the highest citation frequencies include ‘Sung H, 2021, CA Cancer J Clin’, which offers authoritative global cancer statistics, ‘Bass AJ, 2014, Nature’, known for its molecular subtyping of gastric cancer, and ‘Bettegowda C, 2014, Sci Transl Med’, which is seminal in ctDNA (ctDNA) analysis. The density visualization (Fig.9b) further emphasizes the intellectual hotspots of the field. Denser and warmer areas highlight highly co-cited references that serve as scientific cornerstones, suggesting that foundational studies in ctDNA detection, biomarker validation, and clinical application continue to inform ongoing research. Additionally, the top 10 most co-cited references in this field (Table 7) further corroborate the visual findings. Collectively, this analysis reflects the interdisciplinary nature of the field, integrating cancer epidemiology, molecular oncology, and LB technology.

Discussion

General information
GC, a common global cancer, has a poor prognosis from late - stage diagnosis, reducing overall survival [24]. Obtaining representative biological samples to investigate the biological characteristics of GC and guide personalized treatment remains a major focus of research [24, 25]. In the past few years, there has been an increasing acknowledgment of the crucial function that LB serves in the clinical management of patients with GC. Compared to traditional tissue biopsy, liquid biopsy (LB) offers a non-invasive approach, which has the advantages of simple sampling, high repeatability, and low risk. It assists in GC diagnosis and dynamic monitoring, providing valuable diagnostic and prognostic insights into disease progression [26, 27].
This study presents a visual bibliometric analysis of 360 publications on LB in GC (WOSCC, 2000–2025), analyzing trends, collaborations, and research themes to elucidate current hotspots and future directions. LB represents an exciting new area in cancer diagnosis and management with great promise for precision medicine [26, 28]. The data in our study reveal that the publication output reflects the emergence of liquid biopsy (LB) as a pivotal tool in gastric cancer (GC) precision medicine. After a nascent period with low activity (2006–2014), annual publications increased rapidly from 2016 onward. This growth underscores the technological maturation of LB and the growing clinical demand for non-invasive tools. The peak years of 2023 and 2025 highlight its current prominence for early detection, prognosis, and treatment guidance in GC.

Function and diagnostic potential of LB in GC
LB is a good tool for early detection of GC and is expected to overcome key limitations of traditional methods, such as the invasiveness of endoscopy and radiation exposure of imaging [7]. LB analyzes ctDNA, CTCs, exosomes, and non-coding RNAs (ncRNAs) from blood, saliva, or gastric juice, offering a non-invasive approach to identify molecular alterations indicative of early-stage GC [25]. For example, some studies found that the expression levels of miR-129 and lncRNA-AA174084 in the gastric juice of GC patients were significantly higher than those of healthy people, and showed the potential to diagnose GC [29, 30]. In addition, ctDNA, cfDNA, circular RNAs, and miRNAs can also serve as molecular biomarkers for early GC [7, 31, 32]. Among the retrieved publications, the most cited is Ma et al. [33], which developed a dual-capture strategy using EpCAM and EGFR antibodies on nanostructured substrates to enhance the sensitivity and specificity of capturing EpCAM-positive circulating tumor cells (CTCs). This approach effectively addresses the challenge of low tumor load in CTC-based diagnostics [34] and demonstrates potential for early diagnosis and prognosis monitoring in GC. In their 2025 mini-review, Peng et al. [35] highlight emerging blood-based biomarkers (CTCs, ctDNA, cell-free RNA, and exosomal RNAs) as promising non-invasive tools for early GC diagnosis, contrasting them with limited conventional serological markers (e.g., CEA, CA19-9, CA72-4) and noting the need for standardized protocols. The significant citation of this work confirms the field’s focus on these biomarkers.
In terms of prognostic evaluation, the count and characteristics of circulating tumor cells (CTCs), such as CD44-expressing subpopulations, are significantly associated with survival in gastric cancer patients. Elevated preoperative CTC levels often correlate with poorer prognosis and a higher risk of recurrence [7]. Conversely, dynamic changes in ctDNA can also predict recurrence, where persistently high post-operative levels frequently indicate residual tumor or early metastasis [7, 33, 36]. For instance, a study demonstrated that HER2 copy number alterations in ctDNA are predictive of trastuzumab treatment efficacy [37]. Liquid biopsy can track the efficacy of targeted therapy or chemotherapy in real time. Research has demonstrated that the clearance of specific ctDNA mutations (e.g., EGFR, RAS) is associated with treatment response, with the emergence of resistance mechanisms (e.g., MET amplification) informing subsequent therapy adjustments [7, 36, 38, 39].

Clinical challenges and hotspots
Conducting keyword analysis is of great importance as it enables us to understand the internal structure of a field, identify research hotspots, and provide guidance for future studies [13]. In this study, ctDNA, cfDNA, exosomes, and miRNA emerge as core technical terms, highlighting their central roles in current research. The frequent occurrence of terms such as “diagnosis”, “prognosis”, and “clinical significance” reflects a strong investigation focus in this field. The integration of molecular features (e.g., mutations) with therapeutic endpoints (e.g., prognosis, drug resistance) indicates a clear shift toward personalized medicine [40–42].
Based on the literature reviewed in this study, we identify several persistent challenges in the application of LB for GC [7, 43, 44]: (1) Limited Sensitivity: the concentration of circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) in bodily fluids is exceptionally low in early-stage GC patients, leading to potential false negatives with current technologies. (2) Lack of Standardization: the absence of unified protocols for sample processing and detection methodologies compromises the comparability of results across studies. (3) Insufficient Biomarker Validation: The reliability of many biomarkers remains unconfirmed, as most studies are based on small sample sizes, underscoring the need for validation in large-scale clinical trials.
Consequently, future research should prioritize the following directions [7, 45–47]: (1) Integrated Multi-omics and artificial Intelligence: Efforts should focus on multi-omics integration (e.g., genomic and epigenomic analyses) and novel targets, combined with artificial intelligence to enhance analytical accuracy. (2) Alternative Biofluid Exploration: Investigating the diagnostic value of alternative bodily fluids, such as gastric juice, peritoneal lavage fluid, and urine, which could compensate for the limitations of blood-based assays. (3) Shift from Diagnosis to Monitoring: The research focus should expand from mere diagnosis to dynamic therapy monitoring, for instance, in the context of immunotherapy.

Limitations
There are some limitations in this study, which should be noted. Firstly, only English-written articles and reviews recorded in the WOSCC database were incorporated into this study. Although this method may have missed out on several valuable studies, considering that WOSCC is the most frequently employed database for scientometric analysis and encompasses the vast majority of studies [48], we believe it does not have a substantial influence on the general trend. Secondly, our study was limited to English publications, potentially omitting significant non-English evidence. Thirdly, due to the delay in citation volume, recently published high-quality studies may not have received the due attention, and it will be necessary to update them accordingly in subsequent research.

Conclusion
In conclusion, LB in GC is entering a phase of rapid development. LB has emerged as a promising non-invasive tool for GC management, offering some advantages in early detection, prognosis assessment, treatment monitoring, and resistance mechanism analysis. Despite its potential, challenges such as standardization, sensitivity in early-stage detection remain. Future research should focus on integrating multi-omics and artificial intelligence approaches to enhance clinical utility. In the future, LB is poised to enhance diagnostic precision and personalized treatment strategies for GC, with potential benefits for patient prognosis.