EBV persistence in gastric cancer cases conventionally classifed as EBER-ISH negative
Background: The Epstein-Barr virus (EBV) causes various B-cell lymphomas and epithelial malignancies, including gastric cancer (GC) at frequencies ranging from 5 to 10% in adenocarcinomas (ADK) to 80% in GC with lymphoid stroma (GCLS). Using high-sensitivity methods, we recently detected EBV traces in a large cohort of EBV-negative B-cell lymphomas, suggesting a hit-and-run mechanism.
Methods: Here, we used routine and higher-sensitivity methods [droplet digital PCR (ddPCR) for EBV segments on microdissected tumour cells and RNAscope for EBNA1 mRNA] to assess EBV infection in a cohort of 40 GCs (28 ADK and 12 GCLS).
Results: ddPCR documented the presence of EBV nucleic acids in rare tumour cells of several cases conventionally classifed as EBV-negative (ADK, 8/26; GCLS, 6/7). Similarly, RNAscope confrmed EBNA1 expression in rare tumour cells (ADK, 4/26; GCLS, 3/7). Finally, since EBV induces epigenetic changes that are heritable and retained after complete loss of the virus from the host cell, we studied the methylation pattern of EBV-specifcally methylated genes (Timp2, Eya1) as a mark of previous EBV infection. Cases with EBV traces showed a considerable level of methylation in Timp2 and Eya1 genes that was similar to that observed in EBER-ISH positive cases and greater than cases not featuring any EBV traces.
Conclusions: These fndings suggest that: (a) EBV may contribute to gastric pathogenesis more widely than currently acknowledged and (b) indicate the methylation changes as a mechanistic framework for how EBV can act in a hit-and-run manner. Finally, we found that the viral state was of prognostic signifcance in univariate and multivariate analyses.
History
Publication
Infectious Agents and Cancer, 2022, 17:57Publisher
Springer NatureAlso affiliated with
- Health Research Institute (HRI)
Sustainable development goals
- (3) Good Health and Well-being