PanNET : Molecular Genetics
Molecular Genetics of Pancreatic Neuroendocrine Tumors (PanNETs): PanNETs differ from ductal adenocarcinomas of pancreas in their molecular pathogenesis. PanNETs don't carry mutations in KRAS, CDKN2A, or SMAD4 genes. TP53 mutations are also less common in PanNETs. MEN1 Gene: PanNETs in MEN1 syndrome and about 40% of sporadic (non-inherited) PanNETs have mutations in MEN1 gene - a tumor suppressor gene that codes for Menin. Menin is a 610-amino acid nuclear protein involved in cell growth, cell cycle regulation, genomic stability, and apoptosis. In MEN type 1, virtually 100% of cases show PanNET at autopsy. Clinical manifestations are seen in 30%-75% of cases. Patients have multiple individual tumors, most of which are non-functioning; however, at least one functioning PanNET is seen in majority of cases. DAXX and ATRX Mutations : About 40% of PanNETs have mutually exclusive mutations in either DAXX (death-domain-associated protein) or ATRX (α-thalassemia/mental retardation syndrome X-linked) genes. Their protein products regulate chromatin remodeling at telomeric and pericentromeric regions. DAXX and ATRX mutations lead to chromosomal instability. About this image: Loss of DAXX expression (nuclear) in tumor cells by immunohistochemistry is a sensitive and specific marker of DAXX mutations in PanNETs. Normal DAXX expression in the stromal cells serves as a nice internal positive control. Image courtesy of: Dr. Aatur Singhi (@PancPathologist); used with permission. Molecular genetics of PanNETS - continued in next image.