title: MEN1 gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids.
abstract: BACKGROUND
  MEN1 gene alterations have been implicated in lung carcinoids, but their effect on gene expression and disease outcome is unknown.
  
  
  OBJECTIVE
  Our objective was to analyze MEN1 gene and expression anomalies in lung neuroendocrine neoplasms and their correlations with clinicopathologic data and disease outcome.
  
  
  METHODS
  We examined 74 lung neuroendocrine neoplasms including 58 carcinoids and 16 high-grade neuroendocrine carcinomas (HGNECs) for MEN1 mutations (n = 70) and allelic losses (n = 69), promoter hypermethylation (n = 65), and mRNA (n = 74) expression. Results were correlated with disease outcome.
  
  
  RESULTS
  MEN1 mutations were found in 7 of 55 (13%) carcinoids and in 1 HGNEC, mostly associated with loss of the second allele. MEN1 decreased expression levels correlated with the presence of mutations (P = .0060) and was also lower in HGNECs than carcinoids (P = .0024). MEN1 methylation was not associated with mRNA expression levels. Patients with carcinoids harboring MEN1 mutation and loss had shorter overall survival (P = .039 and P = .035, respectively) and low MEN1 mRNA levels correlated with distant metastasis (P = .00010) and shorter survival (P = .0071). In multivariate analysis, stage and MEN1 allelic loss were independent predictors of prognosis.
  
  
  CONCLUSIONS
  Thirteen percent of pulmonary carcinoids harbor MEN1 mutation associated with reduced mRNA expression and poor prognosis. Also in mutation-negative tumors, low MEN1 gene expression correlates with an adverse disease outcome. Hypermethylation was excluded as the underlying mechanism.
authors.affiliation: Departments of Molecular Cell Biology (D.R.A.S., M.E.R.H., F.C.S.R.) and Pathology (E.-J.M.S., M.v.E.), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; Applied Research on Cancer-NET Research Centre and Department of Pathology and Diagnostics (A.S., V.C.), University and Hospital Trust of Verona, 37134 Verona, Italy; Laboratory of Bioinformatics and Computational Genomics (W.V.C.), Ghent University, Belgium; Department of Oncology (G.G., M.P., M.V.), Division of Pathology, University of Turin at San Luigi Hospital, Orbassano, Torino, Italy; and Department of Pathology (A.P.), University of Bern, Bern, Switzerland.
authors.forename: Dorian R A
authors.initials: DR
authors.lastname: Swarts
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Gaia
authors.initials: G
authors.lastname: Gatti
authors.forename: Mieke E R
authors.initials: ME
authors.lastname: Henfling
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
mesh_terms: D000483:Alleles; D002276:Carcinoid Tumor / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015996:Survival Rate
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins