Thus, it appears inescapable that mutations in single genes such as MEN1 alone cannot cause insulinoma; instead, “hits” in multiple genes are likely required: MEN1 is just one of many core polycomb/trithorax genes (e.g., MEN1, KDM6A, YY1, EZH2, PCGF5, KTM2C, CREBBP etc.), which may contribute to the insulinoma phenotype. This evidence concerns the gene EZH2 and pancreatic insulinoma.