title: Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.
abstract: BACKGROUND
  An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.
  
  
  OBJECTIVE
  The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).
  
  
  METHODS
  This was a multicenter, international, collaborative study.
  
  
  METHODS
  The study was conducted in 34 university endocrinology and genetics departments in nine countries.
  
  
  METHODS
  Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.
  
  
  METHODS
  Presence/absence and description of AIP gene mutations were the main outcome measures.
  
  
  METHODS
  There was no intervention.
  
  
  RESULTS
  Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
  
  
  CONCLUSIONS
  AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Vanbellinghen
authors.forename: Sok Kean
authors.initials: SK
authors.lastname: Khoo
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jaffrain-Rea
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Naves
authors.forename: Mirtha A
authors.initials: MA
authors.lastname: Guitelman
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Philippe
authors.initials: P
authors.lastname: Emy
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Guido
authors.initials: G
authors.lastname: Tamburrano
authors.forename: Gérald
authors.initials: G
authors.lastname: Raverot
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Wouter
authors.initials: W
authors.lastname: De Herder
authors.forename: Alfred
authors.initials: A
authors.lastname: Penfornis
authors.forename: Enrica
authors.initials: E
authors.lastname: Ciccarelli
authors.forename: Bruno
authors.initials: B
authors.lastname: Estour
authors.forename: Pierre
authors.initials: P
authors.lastname: Lecomte
authors.forename: Blandine
authors.initials: B
authors.lastname: Gatta
authors.forename: Olivier
authors.initials: O
authors.lastname: Chabre
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Sabaté
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia Basavilbaso
authors.forename: Graciela
authors.initials: G
authors.lastname: Stalldecker
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.forename: Piero
authors.initials: P
authors.lastname: Ferolla
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Wémeau
authors.forename: Philippe
authors.initials: P
authors.lastname: Caron
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Sadoul
authors.forename: Adriana
authors.initials: A
authors.lastname: Oneto
authors.forename: Françoise
authors.initials: F
authors.lastname: Archambeaud
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Olga
authors.initials: O
authors.lastname: Sinilnikova
authors.forename: Carmen Fajardo
authors.initials: CF
authors.lastname: Montañana
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavagnini
authors.forename: Vaclav
authors.initials: V
authors.lastname: Hana
authors.forename: Angela
authors.initials: A
authors.lastname: Solano
authors.forename: Dreanina
authors.initials: D
authors.lastname: Delettieres
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Luccio-Camelo
authors.forename: Armando
authors.initials: A
authors.lastname: Basso
authors.forename: Vincent
authors.initials: V
authors.lastname: Rohmer
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D018095:Germ-Line Mutation / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D013006:Growth Hormone