The conundrum of the Epstein-Barr virus-associated gastric carcinoma in the Americas

// Gonzalo Carrasco-Avino 1, 2 , Ismael Riquelme 3, 4 , Oslando Padilla 5 , Miguel Villaseca 4 , Francisco R. Aguayo 1, 6 and Alejandro H. Corvalan 1, 7, 8 1 Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Catolica de Chile, Santiago, Chile 2 Department of Pathology, Faculty of Medicine, Universidad de Chile, Santiago, Chile 3 Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile 4 Department of Pathology, Universidad de la Frontera, Temuco, Chile 5 Department of Public Health, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile 6 Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, Santiago, Chile 7 UC-Center for Investigational Oncology (CITO), Pontificia Universidad Catolica de Chile, Santiago, Chile 8 Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile Correspondence to: Alejandro H. Corvalan, email: corvalan@med.puc.cl Keywords: gastric cancer, Epstein-Barr virus, americas, molecular classification, phylogeographic diversity Received: December 20, 2016 Accepted: May 29, 2017 Published: June 15, 2017 ABSTRACT Epstein-Barr virus-associated gastric carcinoma shows a higher prevalence in the Americas than Asia. We summarize all studies of Epstein Barr virus-associated gastric carcinoma in the Americas, focusing on host characteristics, environmental associations and phylogeographic diversity of Epstein-Barr virus strains. In the Americas, the prevalence of Epstein Barr virus-associated gastric carcinoma is 11.4%, more frequent in males and portray predominantly diffuse-type histology. EBERs, EBNAs, BARTs and LMP are the highest expressed genes; their variations in healthy individuals may explain the phylogeographic diversity of Epstein-Barr virus across the region. Gastric cancer cases harbor exclusively the western genotype (subtype D and kept Xho I site), suggesting a disrupted co-evolution between the pathogen and its host. Epstein-Barr virus-associated gastric carcinoma molecular subtype cases from The Cancer Genome Atlas display PIK3CA gene mutations, amplification of JAK2, PD-L1 and PD-L2 and CpG island methylator phenotype, leading to more extensive methylation of host and viral genomes than any other subtypes from the study. Environmental conditions include negative- and positive- associations with being firstborn child and smoking, respectively. A marginal association with H. pylori has also been reported. Lymphoepithelioma-like carcinoma is associated with Epstein Barr virus in 80%–86% of cases, most of which have been included as part of Epstein Barr virus-associated gastric carcinoma series (prevalence 1.1%–7.6%). Whether these cases represent a variant of Epstein-Barr virus-associated gastric carcinoma is discussed. We propose novel research strategies to solve the conundrum of the high prevalence of Epstein-Barr virus-associated gastric carcinoma in the Americas.