Homo sapiens Exome. Homo sapiens

Gastric carcinogenesis is etiologically associated with two distinctinfectious agents, *Helicobacter pylori *and Epstein-Barr virus, and isinduced by the accumulation of multiple genetic and epigenetic alterations.While various molecular events have been identified in gastric cancer,their interaction needs to be fully elucidated. This study wasdesigned to identifygenetic mutations specific for DNA methylation epigenotypes using exometargeted sequencing combined with both genome-wide DNA methylation analysisand immunohistochemistry on specimens from patients with gastric cancer. Toclarify the interaction between genetically/epigenetically inactivatedgenes and *KRAS* activation, we screened critical genes foroncogene-induced senescence using a shRNA library in activated RAS*-*induciblehuman fibroblasts, *in vitro*. We believe that our study makes asignificant contribution to the literature because our findings indicatethat gastric cancer was clustered into four methylation epigenotypes (MEs):extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremelylow-ME (E-LME). In cases with loss of MLH1 expression, the coupling between*KRAS* activation and genetic/epigenetic inactivation of some criticalgenes contributes to carcinogenesis through disruption of oncogene-inducedpremature senescence, independently of *TP53* dysfunction.