**2. Gastric cancer: novel molecular classifications**

genome as extrachromosomal circular episomes with repression of genes involved in virus replication. If latent persistent infection is established, viral reactivation may occur with the expression of specific EBV genes defining the type of latency in the infected cell. Genes involved in these patterns are shown in **Figure 1** and include the EBV-encoded RNAs (EBERs), the EBV nuclear antigens (EBNAs), the BamH1-A rightward transcripts (BARTs) and the latent membrane protein (LMP)-1, 2A and 2B [3]. These latency-associated patterns have been associated with specific malignancies and in the case of gastric cancer, the virus shows a latency type I/IIab. The EBERs 1 and 2 genes are the most abundant small noncoding RNAs that interact with proteins of the host and are the standard target for EBV detection by in situ hybridization (ISH) [4]. The EBNA-1 and -2 genes are exclusive nuclear proteins expressed in latent infected gastric carcinoma cells and related to the disruption of promyelocytic leukemia nuclear bodies [5]. EBNA-1 is a DNAbinding protein that lacks enzymatic activity although it can interact with some cellular proteins such as CK2 and P32/TAP [6]. Interestingly, EBNA-1 is expressed in all of the EBV-associated tumors and is involved in viral DNA replication, mitotic segregation and transcriptional activation [7]. BART genes encode highly expressed multispliced RNAs whose protein-coding function is controversial [8]. Although some BARTs open reading frames (ORFs) have been predicted, currently it is not clear if any of them can be endogenously translated. In addition, BART genes, small as well as long noncoding RNAs, are highly expressed and associated with oncogenic transformation and immune evasion

10 Gastric Cancer

**Figure 1.** Gene expression patterns at different stages of EBV latency states. The theoretical progression of EBV latency gene expression from initial infection to true latency is described from left to right. The EBV genome is shown in episomal form closed at the terminal repeats (TR). Promoters are shown as white boxes and include the EBNA promoters Cp, Wp and Qp as well as the bidirectional LMPp. Primary mRNA transcripts are shown as dotted lines, while coding regions have been simplified as colored boxes. An expanded list of viral genes expressed in each latency state is listed directly

underneath the representative schematic. Taken from [2] with permission.

The molecular bases of gastric cancer have begun to be unraveled by a comprehensive molecular evaluation of primary tumors [14–20]. As shown in **Figure 2**, the Cancer Genome Atlas (TCGA) network has proposed a novel molecular classification of gastric carcinoma that recognized for the first time a subtype of tumor positive for Epstein-Barr virus, the EBVassociated gastric carcinoma (EBVaGC). This novel subtype of gastric cancer is characterized by frequent PIK3CA gene mutations, amplification of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2), and a unique CpG island methylator phenotype (CIMP) [14, 21].


**Figure 2.** Major features of molecular classification of gastric cancer as proposed by the tumor cancer genome atlas (TCGA) are CIMP: CpG island methylator phenotype, EBV: Epstein-Barr virus, MSI: microsatellite instability, GS: genomically stable and CIN: chromosomal instability. Taken from [20] with permission.
