Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations.
Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
Georgitsi
Marianthi
M
Department of Medical Genetics, Molecular and Cancer Biology Research Program, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland.
Raitila
Anniina
A
Karhu
Auli
A
Tuppurainen
Karoliina
K
Mäkinen
Markus J
MJ
Vierimaa
Outi
O
Paschke
Ralf
R
Saeger
Wolfgang
W
van der Luijt
Rob B
RB
Sane
Timo
T
Robledo
Mercedes
M
De Menis
Ernesto
E
Weil
Robert J
RJ
Wasik
Anna
A
Zielinski
Grzegorz
G
Lucewicz
Olga
O
Lubinski
Jan
J
Launonen
Virpi
V
Vahteristo
Pia
P
Aaltonen
Lauri A
LA
D000172:Acromegaly / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009377:Multiple Endocrine Neoplasia / Q000235:genetics; D009154:Mutation; D010911:Pituitary Neoplasms / Q000208:ethnology / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein