Neuroendocrine tumors of the digestive tract are usually sporadic but can arise in multiple endocrine neoplasia type 1 (MEN1) and more rarely in other syndromes, including von Hippel–Lindau (VHL) syndrome and tuberous sclerosis. MEN1 is a tumor suppressor gene that, when mutated in the germline, predisposes to MEN1 syndrome. Biallelic inactivation of the MEN1 (multiple endocrine neoplasia type 1) gene, usually through a mutation in one allele coupled with the loss of the remaining wild-type allele, occurs with pancreatic NET. Mutations affecting VHL, NF1, and TSC1 genes are associated with an increased risk of developing malignant pancreatic neuroendocrine tumors in patients with von Hippel–Lindau disease, type 1 neurofibromatosis, and tuberous sclerosis syndromes, respectively.

Hereditary forms of neuroendocrine tumors have highlighted the crucial role of genes regulating hypoxia signaling. In von Hippel–Lindau disease, loss of pVHL protein function, which usually tags the hypoxia-inducible factor 1 (HIF1) for proteasomal degradation, results in nuclear accumulation of HIF1α, yielding increased transcription of a number of hypoxia-inducible genes, such as CA-9 and GLUT-1 (glucose transporter 1). In type 1 neurofibromatosis and tuberous sclerosis syndromes, HIF-1α is indirectly activated through mTOR (mammalian target of rapamycin), due to loss of function of NF1 and TSC1 genes. Of note, such cases of familial pNET are acknowledged to be associated with adverse outcome as compared to MEN1 tumors.