Key Takeaways & Executive Findings
- •• A functional EBV proteome microarray covering 72 viral proteins was developed and applied to profile antibody responses in gastric cancer patients, revealing an IgG-skewed humoral signature specific to EBVaGC. • A five-analyte panel (LF2_IgG, BBLF2_IgG, BLRF2_IgG, BPLF1-2_IgA, and BGLF4_IgA) was identified and validated, achieving an AUC of 0.93 in an independent validation set (n=316). • In a community-based screening cohort (n=474), the panel achieved 87.3% sensitivity and 88.3% specificity for distinguishing EBVaGC from non-malignant gastric conditions, with an AUC of 0.94. • The study establishes a serological framework for EBVaGC diagnosis, offering a scalable strategy for population-level screening that could improve clinical management of this virus-driven malignancy.
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) displays unique clinicopathological hallmarks, yet serology-based tools for its detection are still limited. Here, we develop a functional EBV proteome microarray covering 72 viral proteins and apply it to profile antibody responses in 62 gastric cancer patients. The resulting landscape reveals an IgG-skewed humoral signature specific to EBVaGC and identifies 34 EBV antigens exhibiting differential reactivities. Multivariable logistic regression integrates complementary markers into an optimal five-analyte panel (LF2_IgG, BBLF2_IgG, BLRF2_IgG, BPLF1-2_IgA, and BGLF4_IgA) that achieves outstanding discrimination performance (AUC = 0.93) in an independent validation set (n = 316). The panel’s performance is further validated in a community-based screening cohort (n = 474), where it achieves 87.3% sensitivity and 88.3% specificity for distinguishing EBVaGC from non-malignant gastric conditions spanning gastritis to dysplasia (AUC = 0.94). Together, these results establish a serological framework for EBVaGC diagnosis and provide a scalable strategy for population-level screening that could materially improve the management of this virus-driven malignancy.
1. Introduction
Epstein-Barr virus-associated gastric cancer (EBVaGC) is a distinct molecular subtype that accounts for 5%–10% of gastric carcinomas worldwide [1]. It is characterized by pervasive genome-wide DNA hypermethylation, which drives unique tumor biology and pronounced immunogenic profile [2]. This distinct biology underlies the subtype’s exceptional sensitivity to immune checkpoint inhibitors, making EBV status a valuable predictive biomarker in clinical practice [3,4]. Therefore, the precise and timely differentiation of EBVaGC from other subtypes of gastric cancer is of significant implications for treatment selection.
Currently, the diagnostic gold standard of EBVaGC relies on in situ hybridization for Epstein-Barr virus-encoded RNA (EBER) in tumor tissue [5]. However, neoadjuvant treatments administered before surgery often disrupt tumor architecture and reduce the sensitivity of EBER detection [6,7]. In addition, EBV status is typically evaluated in pre-operative biopsy specimens, where limited sampling and intratumoral heterogeneity can lead to false-negative results and consequently low detection rates [8,9]. These challenges underscore the urgent need for rapid, tissue-independent diagnostic assays to reliably identify EBVaGC, thereby improving patient stratification and targeted treatment.
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Pincang Xia, Yingying Yu, Xiaoting Xu, Jiajun Lin, Jiayi Shen, Xinyi Lin, Tao Zhang, Zhaowei Xu, Xian-E Peng, Xu Lin (2026). Discovery and Validation of Biomarkers for Epstein-Barr Virus Associated Gastric Cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026046
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Frequently Asked Questions
What is the significance of this study?
This study identifies and validates a five-biomarker panel for the serological detection of Epstein-Barr virus-associated gastric cancer (EBVaGC), offering a non-invasive diagnostic tool that could improve patient stratification and enable population-level screening.
How was the biomarker panel developed?
The panel was developed using a functional EBV proteome microarray covering 72 viral proteins to profile antibody responses in gastric cancer patients. Multivariable logistic regression integrated complementary markers into an optimal five-analyte panel.
What are the key biomarkers in the panel?
The panel includes antibodies against LF2 (IgG), BBLF2 (IgG), BLRF2 (IgG), BPLF1-2 (IgA), and BGLF4 (IgA).
How well does the panel perform?
The panel achieved an AUC of 0.93 in an independent validation set (n=316) and an AUC of 0.94 in a community-based screening cohort (n=474), with 87.3% sensitivity and 88.3% specificity.
What are the potential clinical applications?
The panel could be used for non-invasive diagnosis of EBVaGC, aiding in treatment selection and enabling large-scale screening programs to detect this subtype early.
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