Abstract: Mounting evidences suggest that the ATRX (α thalassaemia/mental retardation syndrome X linked) and DAXX (death domain associated protein) which encode 2 subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, and multiple endocrine neoplasia type 1 (MEN 1) genes are significantly mutated in most patients with pancreatic neuroendocrine tumors (pNETs), as are genes encoding key molecules of the mammalian target of rapamycin (mTOR) signaling pathway. These mutated genes promote deregulation of epigenetic processes such as chromatin remodeling, histone modification and activation of alternative lengthening of telomeres, and thus combined alteration of these genes may contribute to drive tumorigenesis and metastasis of pNETs which are characterized by complex patterns of phenotypes. These findings may have great significance in the diagnosis and treatment of pNETs and predicting the prognosis, as well as providing clinical implications for targeted cancer therapy.Pancreas; Neuroendocrine neoplasms; Genetic mutation; Epigenetics