title: Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain.
abstract: BACKGROUND
  Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype.
  
  
  OBJECTIVE
  The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs.
  
  
  METHODS
  This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center.
  
  
  METHODS
  Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured.
  
  
  RESULTS
  Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428-610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs.
  
  
  CONCLUSIONS
  MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.
authors.affiliation: Departments of Visceral, Thoracic, and Vascular Surgery (D.K.B., E.P.S., M.A., R.K., B.C., C.L.L., V.F., J.W.) and Gastroenterology (P.H.K.), Division of Endocrinology and Diabetology, University Hospital Giessen and Marburg, Campus Marburg, 35041 Marburg, Germany.
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Emily P
authors.initials: EP
authors.lastname: Slater
authors.forename: Max
authors.initials: M
authors.lastname: Albers
authors.forename: Richard
authors.initials: R
authors.lastname: Knoop
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Chaloupka
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Lopez
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kann
authors.forename: Jens
authors.initials: J
authors.lastname: Waldmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C106158:FOXN3 protein, human; D051858:Forkhead Transcription Factors; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins