Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.
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.
Daly
Adrian F
AF
Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium.
Vanbellinghen
Jean-François
JF
Khoo
Sok Kean
SK
Jaffrain-Rea
Marie-Lise
ML
Naves
Luciana A
LA
Guitelman
Mirtha A
MA
Murat
Arnaud
A
Emy
Philippe
P
Gimenez-Roqueplo
Anne-Paule
AP
Tamburrano
Guido
G
Raverot
Gérald
G
Barlier
Anne
A
De Herder
Wouter
W
Penfornis
Alfred
A
Ciccarelli
Enrica
E
Estour
Bruno
B
Lecomte
Pierre
P
Gatta
Blandine
B
Chabre
Olivier
O
Sabaté
María Isabel
MI
Bertagna
Xavier
X
Garcia Basavilbaso
Natalia
N
Stalldecker
Graciela
G
Colao
Annamaria
A
Ferolla
Piero
P
Wémeau
Jean-Louis
JL
Caron
Philippe
P
Sadoul
Jean-Louis
JL
Oneto
Adriana
A
Archambeaud
Françoise
F
Calender
Alain
A
Sinilnikova
Olga
O
Montañana
Carmen Fajardo
CF
Cavagnini
Francesco
F
Hana
Vaclav
V
Solano
Angela
A
Delettieres
Dreanina
D
Luccio-Camelo
Douglas C
DC
Basso
Armando
A
Rohmer
Vincent
V
Brue
Thierry
T
Bours
Vincent
V
Teh
Bin Tean
BT
Beckers
Albert
A
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*
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D013006:Growth Hormone