Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma

Abstract

A small set of gastric adenocarcinomas (9%) harbor Epstein-Barr virus (EBV) DNA within malignant cells, and the virus is not an innocent bystander but rather is intimately linked to pathogenesis and tumor maintenance. Evidence comes from unique genomic features of host DNA, mRNA, microRNA and CpG methylation profiles as revealed by recent comprehensive genomic analysis by The Cancer Genome Atlas Network. Their data show that gastric cancer is not one disease but rather comprises four major classes: EBV-positive, microsatellite instability (MSI), genomically stable and chromosome instability. The EBV-positive class has even more marked CpG methylation than does the MSI class, and viral cancers have a unique pattern of methylation linked to the downregulation of CDKN2A (p16) but not MLH1. EBV-positive cancers often have mutated PIK3CA and ARID1A and an amplified 9p24.1 locus linked to overexpression of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Multiple noncoding viral RNAs are highly expressed. Patients who fail standard therapy may qualify for enrollment in clinical trials targeting cancer-related human gene pathways or promoting destruction of infected cells through lytic induction of EBV genes. Genomic tests such as the GastroGenus Gastric Cancer Classifier are available to identify actionable variants in formalin-fixed cancer tissue of affected patients.

Figure 1

During latent infection, a very limited repertoire of viral gene is expressed. However, when an infected cell switches into the lytic phase of active viral replication, dozens of viral proteins are expressed that trigger immune recognition and destruction. Cell death may be enhanced by administering the anti-viral drug gancyclovir, a purine analog that is incorporated into DNA strands by DNA polymerase. Viral thymidine kinase (BXLF1) and serine/threonine protein kinase/phosphotransferase (BGLF4) phosphorylate gancyclovir, which then stalls DNA synthesis and triggers apoptosis. Intercellular transfer of phosphorylated gancyclovir can result in death of adjacent cells.