Background

Around 10% of gastric carcinomas (GC) contain Epstein–Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis.

Methods

Plasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative).

Results

Forty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81–0.85 for distinguishing tumor EBV status.

Conclusions

The EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC.

中文翻译：

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EBV相关胃癌中抗爱泼斯坦-巴尔病毒（EBV）抗体特征的鉴定

背景

大约 10% 的胃癌 (GC) 含有 Epstein-Barr 病毒 (EBV) DNA。我们表征了对这种常见感染的 GC 特异性抗体反应，这可能提供一种非侵入性方法来检测 EBV 阳性 GC 并阐明其对致癌作用的贡献。

方法

来自 EBV 阳性 ( n  = 28) 和 EBV 阴性 ( n  = 34) 的拉脱维亚 GC 患者的血浆样本在多微生物核酸可编程蛋白阵列 (EBV-NAPPA) 上针对 85 种 EBV 蛋白进行了免疫分析。将每个样品的抗体反应标准化为与所有抗原的中值信号强度 (MNI) 的比值，血清阳性定义为 MNI ≥ 2。通过酶联免疫吸附剂验证对肿瘤 EBV 状态具有 95% 特异性且灵敏度≥ 20% 的抗体检测（ELISA）并在来自韩国和波兰的独立样本中验证（n  = 24 EBV 阳性，n  = 65 EBV 阴性）。

结果

EBV-NAPPA 在≥ 10% 的 EBV 阳性或 EBV 阴性 GC 患者中检测到 40 种抗 EBV IgG 和 8 种 IgA 抗体，其中 9 种 IgG 抗体可区分肿瘤 EBV 状态。这 9 个中的 8 个经过验证，7 个通过 ELISA 验证：抗 LF2（优势比 = 110.0）、抗 BORF2（54.2）、抗 BALF2​​（44.1）、抗 BaRF1（26.7）、抗 BXLF1（12.8） 、抗 BRLF1 (8.3) 和抗 BLLF3 (5.4)。前三名的受试者工作特征曲线下面积为 0.81-0.85，用于区分肿瘤 EBV 状态。

结论

EBV 相关的 GC 特异性体液反应专门针对裂解周期即早期和早期抗原，这与其他 EBV 相关恶性肿瘤如鼻咽癌和淋巴瘤的体液反应主要针对晚期裂解抗原不同。特异性抗 EBV 抗体可用于 EBV 阳性 GC 的临床诊断、流行病学研究和基于免疫的精准治疗。