Identification of anti-epstein-barr virus (EBV) antibody signature in EBV-associated gastric carcinoma

Lusheng Song, Minkyo Song, M. Constanza Camargo, Jennifer Van Duine, Stacy Williams, Yunro Chung, Kyoung Mee Kim, Jolanta Lissowska, Armands Sivins, Weimin Gao, Kailash Karthikeyan, Jin Park, Marcis Leja, Jeffrey I. Cohen, Joshua LaBaer, Ji Qiu, Charles S. Rabkin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalGastric Cancer
DOIs
StateAccepted/In press - 2021

Keywords

  • EBV-positive tumors
  • Molecular subtyping
  • Noninvasive biomarkers
  • Viral reactivation

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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