In the present review, we summarized the mutations of epigenetic regulators, including ARID1A, SMARCA2, SMARCA4, KDM6A, KMT2C, KMT2D, and BRD4 in GI cancers—in particular, pancreatic cancer—and found these regulators to be frequently mutated. Here, KMT2C is linked to familial pancreatic carcinoma.