Importantly, GEP-NECs exhibit key genetic aberrations identical to the non-neuroendocrine carcinomas arising in the same sites, such as BRAF and APC mutations in colorectal NECs [11, 12, 29, 45, 57, 84–88], KRAS mutation in colorectal and pancreatic NECs [9, 11, 12, 20, 29, 45, 55, 57], NOTCH1 mutation in esophageal NECs [11, 12, 57], and E74-like ETS transcription factor 3 (ELF3) mutation in ampullary NECs [10, 89] (Table 4 and Fig. 1), suggesting the hypothesis that GEP-NECs and non-neuroendocrine carcinomas originate from common clonal precursors in the same organ [3, 10, 90]. This evidence concerns the gene ELF3 and pancreatic endocrine carcinoma.