Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?

Abstract

Approximately 90% of the world population is infected by Epstein-Barr virus (EBV). Usually, it infects B lymphocytes, predisposing them to malignant transformation. Infection of epithelial cells occurs rarely, and it is estimated that about to 10% of gastric cancer patients harbor EBV in their malignant cells. Given that gastric cancer is the third leading cause of cancerrelated mortality worldwide, with a global annual incidence of over 950,000 cases, EBV-positive gastric cancer is the largest group of EBV-associated malignancies. Based on gene expression profile studies, gastric cancer was recently categorized into four subtypes; EBV-positive, microsatellite unstable, genomically stable and chromosomal instability. Together with previous studies, this report provided a more detailed molecular characterization of gastric cancer, demonstrating that EBV-positive gastric cancer is a distinct molecular subtype of the disease, with unique genetic and epigenetic abnormalities, reflected in a specific phenotype. The recognition of characteristic molecular alterations in gastric cancer allows the identification of molecular pathways involved in cell proliferation and survival, with the potential to identify therapeutic targets. These findings highlight the enormous heterogeneity of gastric cancer, and the complex interplay between genetic and epigenetic alterations in the disease, and provide a roadmap to implementation of genome-guided personalized therapy in gastric cancer. The present review discusses the initial studies describing EBV-positive gastric cancer as a distinct clinical entity, presents recently described genetic and epigenetic alterations, and considers potential therapeutic insights derived from the recognition of this new molecular subtype of gastric adenocarcinoma.

Prospective observation: Clinical utility of plasma Epstein–Barr virus DNA load in EBV‐associated gastric carcinoma patients

“…Another international pooled analysis included 4,599 GC patients from 13 studies and found that tumor EBV positivity was 8.2% . Compared to EBV‐negative gastric carcinoma (EBVnGC), EBV associated gastric carcinomas (EBVaGCs) reportedly affects younger males, is of the preferential Lauren diffuse subtype, and its predominance is in the proximal and remnant stomach . Most studies showed a favorable survival for the EBVaGC patients, although some study reported no relationship between EBV infection and survival or even worse .…”

“…5 Compared to EBV-negative gastric carcinoma (EBVnGC), EBV associated gastric carcinomas (EBVaGCs) reportedly affects younger males, is of the preferential Lauren diffuse subtype, and its predominance is in the proximal and remnant stomach. 4,[6][7][8][9] Most studies showed a favorable survival for the EBVaGC patients, 5,[10][11][12] although some study reported no relationship between EBV infection and survival or even worse. 13,14 EBVaGC are generally defined by the presence of EBV in gastric carcinoma cells by in situ hybridization (ISH) targeting EBV-encoded RNA (EBER).…”

<p>Pathological Complete Response After a Single Dose of Anti-PD-1 Therapy in Combination with Chemotherapy as a First-Line Setting in an Unresectable Locally Advanced Gastric Cancer with PD-L1 Positive and Microsatellite Instability</p>

“…It has been reported that 8% to 10% GC were associated with EBV infection. 20 The Cancer Genome Atlas project also revealed that amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2) was frequently observed in EBVpositive gastric adenocarcinoma. 19 However, in our patient, EBV was absence in tumor cells.…”

Comparison of TGF-β, IL-10 levels and LMP-1 in gastric and oropharyngeal carcinoma associated with EBV infection

“…Nowadays, more than 950,000 cases of gastric adenocarcinoma are diagnosed in the world annually and the relationship between this type of cancer and EBV is estimated to be around 10%. A meta-analysis comprising 9,738 cases evaluated the frequency of EBV-associated gastric cancer (EBVaGC) at the level of 8.8% [4]. Every year, EBVaGC Increasing interest has been focused on the Epstein-Barr Virus (EBV)-associated cancers, including oropharyngeal cancer (OPC) and gastric cancer (GC).…”