title: Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.
abstract: Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.
authors.affiliation: Division of Internal Medicine and Dermatology, Department of Internal Medicine, University Medical Center Utrecht, Internal post number L.00.408, PO Box 85500, 3508 GA Utrecht, The Netherlands Division of Biomedical Genetics, Department of Molecular Cancer Research Division of Surgical Specialties, Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C R C
authors.initials: CR
authors.lastname: Pieterman
authors.forename: E B
authors.initials: EB
authors.lastname: Conemans
authors.forename: K M A
authors.initials: KM
authors.lastname: Dreijerink
authors.forename: J M
authors.initials: JM
authors.lastname: de Laat
authors.forename: H Th M
authors.initials: HT
authors.lastname: Timmers
authors.forename: M R
authors.initials: MR
authors.lastname: Vriens
authors.forename: G D
authors.initials: GD
authors.lastname: Valk
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004379:Duodenal Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism / Q000473:pathology*; D009378:Neoplasms, Multiple Primary / Q000378:metabolism / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013899:Thoracic Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins
keywords: MEN1; duodenopancreatic NET; epigenetics; lung NET; menin; multiple endocrine neoplasia type 1; natural history; neuroendocrine tumors; pancreatic NET; thymic NET