Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C ( ) as a frequently mutated gene and examined its role in DGA progression. We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C ( ) was analyzed in DGA cell lines and in patient tumors. was the most frequently mutated gene (11 of 27 tumors 41%). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( = 0.023) and worse overall survival ( = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.