Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (<em>TP53</em>, <em>ARID1A</em> and <em>CDH1</em>) and new (<em>MUC6</em>, <em>CTNNA2</em>, <em>GLI3</em>, <em>RNF43</em> and others) significantly mutated driver genes. Specifically, we found <em>RHOA</em> mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (<em>P</em> &lt; 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which <em>RHOA</em> and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.