Inactivation of the retinoblastoma pathway was originally implicated in PanNET tumorigenesis based on studies of double knockout mice having inactivation of Rb1 and Tp53: Tp53+/−; Rb+/− and Tp53−/−; Rb+/− mice developed non-invasive islet carcinoma, together with other neuroendocrine and non-neuroendocrine tumors [13]. This evidence concerns the gene TP53 and neuroendocrine neoplasm.