**1. Introduction**

Despite a decline in the incidence in past decades, gastric cancer remains a major health problem globally [1, 2], being the fifth most common type of cancer worldwide, with almost one million new cases estimated to have occurred in 2012, according to Globocan [3]. Furthermore, stomach cancer represents the third leading cause of cancer death in both sexes worldwide (723,000 deaths) [3].

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According to the World Health Organization classification, the vast majority of gastric cancers are adenocarcinomas, divided into papillary, tubular, mucinous (colloid), and poorly cohesive carcinomas (including signet-ring cell carcinoma and other variants) [4]. Although it was proposed a long time ago (1965), the Lauren classification is still widely used in clinical practice and subdivides gastric carcinomas into intestinal and diffuse types, associated with different pathogenesis, ways of spreading, and outcome [5]. Unfortunately, these two classification systems have little clinical impact, making the development of classifiers that can define prognosis and guide patient's treatment as an urgent need.

Literature data have demonstrated that the development of gastric cancer is associated in the majority of cases with infectious agents such as the Gram-negative spiral bacterium *Helicobacter pylori* (most often) [6] and Epstein-Barr virus (EBV) (about 9% of all cases of gastric cancer) [7]. Only a small percentage of gastric cancer patients (hereditary cases) are associated with germline mutation in E-cadherin (CDH1) [8] or mismatch repair genes (Lynch syndrome) [9]. In contrast to the familial clustering of gastric cancer, sporadic mismatch repair-deficient gastric tumors present epigenetic silencing of hMLH1 and p16 in the context of a CpG island methylator phenotype (CIMP) [10].

Due to a lack of early specific clinical features, most patients with gastric cancer are diagnosed in advanced stages, resulting in poor 5-year survival rates [11], with a median survival of less than 1 year in case of metastatic stage IV patients [12–14]. Nowadays, survival has gained only minor improvement despite the advances in diagnostic techniques, the multidisciplinary therapeutic management, and the development of novel molecular targeted treatment agents.

Unfortunately, despite modern treatments, less than a quarter of gastric cancer patients survive longer than 5 years after surgery. Gastric cancer represents a complex disease, showing major differences in their tumor cell behavior and responses to chemotherapy.

Recent data have demonstrated that gastric tumors present a high molecular heterogeneity involved both in the process of carcinogenesis and cancer spread. By identifying the specific molecular patterns of the tumor, it is possible to assess its behavior, the prognosis of the patient, and also to decide the most appropriate treatment, a much more personalized one. It is well known that in the pathogenesis of stomach cancers many different genetic mutations, epigenetic alterations, as well as dysregulated signaling pathways are involved, each of these molecular abnormalities acting in a different stage of the disease.

Currently, novel therapeutic agents that target some of these aberrant molecular signaling pathways are already part of the standard treatment of gastric cancer, while others remain to prove their therapeutic efficacy in the setting of clinical trials [15].
