Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations have long been associated with apparently sporadic pituitary adenomas (PAs) with a prevalence range of 0-12%. The aim of this study was to evaluate the frequency of germline AIP variations in a large cohort of apparently sporadic PAs diagnosed before the age of 40 years, who did not exhibit hypercalcemia and/or MEN1 syndrome components during long-term follow-up.
Materials and Methods:
A total of 97 patients, diagnosed with functional PAs ≤40 years old, composed of somatotropinoma (n = 55), prolactinoma (n = 25), and corticotrophinoma (n = 17), were recruited for this study. Fifty-one of these patients [somatotropinoma (n = 30), prolactinoma (n = 15), and corticotrophinoma (n = 11)] were previously reported as AIP mutation-negative by Sanger sequencing. The entire coding sequence of the AIP gene, along with exon/intron boundaries and the untranslated regions of 41 newly recruited patients, were sequenced for germline variations. In addition, all patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in the AIP gene.
Results:
The AIP c.911G>A: p.Arg304Gln (rs104894190) variant was detected in only two patients with functional PA: one with somatotropinoma [in 1/55 (1.8%)] and one with prolactinoma [in 1/25 (4%)]. None of the corticotrophinomas revealed AIP gene alterations. Thus, the overall prevalence of AIP variation was 2.1% in our cohort.
Conclusions:
Germline AIP gene variations among Turkish patients with apparently sporadic PAs are relatively rare among patients ≤40 years old. None of the patients in our cohort revealed any obviously pathogenic AIP variants.
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References
1.
AfloreiED, KlapholzB, ChenC, et al. (2018) In vivo bioassay to test the pathogenicity of missense human AIP variants. J Med Genet, 55:522-529.
2.
AraujoPB, KasukiL, de Azeredo LimaCH, et al. (2017) AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation. Endocr Connect, 6:914-925.
3.
BarlierA, VanbellinghenJF, DalyAF, et al. (2007) Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab, 92:1952-1955.
4.
BeckersA, AaltonenLA, DalyAF, et al. (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev, 34:239-277.
5.
BolgerGB, BizziMF, PinheiroSV, et al. (2016) cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Endocr Relat Cancer, 23:419-431.
6.
CaiF, ZhangYD, ZhaoX, et al. (2013) Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis. Eur J Endocrinol, 169:867-884.
7.
CasanuevaFF, MolitchME, SchlechteJA, et al. (2006) Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf), 65:265-273.
8.
CazabatL, BouligandJ, SalenaveS, et al. (2012) Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. J Clin Endocrinol Metab, 97:663-670.
9.
CazabatL, LibèR, PerlemoineK, et al. (2007) Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol, 157:1-8.
10.
ChahalHS, StalsK, UnterländerM, et al. (2011) AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med, 364:43-50.
11.
CunyT, PertuitM, Sahnoun-FathallahM, et al. (2013) Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. Eur J Endocrinol, 168:533-541.
12.
DalyAF, Jaffrain-ReaML, CiccarelliA, et al. (2006) Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab, 9:3316-3332.
13.
DalyAF, TichomirowaMA, PetrossiansP, et al. (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab, 95:373-383.
14.
DalyAF, VanbellinghenJF, KhooSK, et al. (2007) Aryl hydrocarbon receptor interacting protein gene mutations in familial isolated pituitary adenomas:analysis in 73 families. J Clin Endocrinol Metab, 92:1891-1896.
15.
FoltranRK, AmorimPVGH, DuarteFH, et al. (2018) Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas. Braz J Med Biol Res, 51:e7427.
16.
GeorgitsiM, HeliövaaraE, PaschkeR, et al. (2008) Large genomic deletions in AIP in pituitary adenoma predisposition. J Clin Endocrinol Metab, 93:4146-4151.
17.
GeorgitsiM, RaitilaA, KarhuA, et al. (2007) Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc Natl Acad Sci USA, 104:4101-4105.
18.
Hernández-RamírezLC, GabrovskaP, DénesJ, et al. (2015) Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab, 100:1242-1254.
19.
Hernández-RamírezLC, MartucciF, MorganRM, et al. (2016) Rapid proteasomal degradation of mutant proteins is the primary mechanism leading to tumorigenesis in patients with missense AIP mutations. J Clin Endocrinol Metab, 101:3144-3154.
20.
Hernández-RamírezLC, MorganRML, BarryS, et al. (2018) Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. Oncotarget, 9:9177-9198.
21.
IacovazzoD, CaswellR, BunceB, et al. (2016) Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun, 4:56.
22.
IgrejaS, ChahalHS, KingP, et al. (2010) Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat, 31:950-960.
23.
Jaffrain-ReaML, Di StefanoD, MinnitiG, et al. (2002) A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas. Endocr Relat Cancer, 9:103-113.
24.
KaracaZ, TaheriS, TanriverdiF, et al. (2015) Prevalence of AIP mutations in a series of Turkish acromegalic patients: are synonymous AIP mutations relevant?. Pituitary, 18:831-837.
25.
KatznelsonL, AtkinsonJL, CookDM, et al. (2011) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly—2011 update. Endocr Pract, 4:1-44.
26.
KatznelsonL, LawsERJr, MelmedS, et al. (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab, 99:3933-3951.
27.
LandrumMJ, LeeJM, RileyGR, et al. (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res, 42:980-985.
28.
LecoqAL, KamenickýP, Guiochon-MantelA, et al. (2015) Genetic mutations in sporadic pituitary adenomas—what to screen for?. Nat Rev Endocrinol, 11:43-54.
29.
LeontiouCA, GueorguievM, van der SpuyJ, et al. (2008) The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab, 93:2390-2401.
30.
MarquesP, BarryS, RonaldsonA, et al. (2018) Emergence of pituitary adenoma in a child during surveillance: clinical challenges and the family members' view in an AIP mutation-positive family. Int J Endocrinol, 2018:8581626.
31.
MelmedS, CasanuevaFF, HoffmanAR, et al. (2011) Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 96:273-288.
32.
MorganRM, Hernández-RamírezLC, TrivellinG, et al. (2012) Structure of the TPR Domain of AIP: lack of client protein interaction with the C-Terminal α-7 Helix of the TPR Domain of AIP is sufficient for pituitary adenoma predisposition. PLoS One, 7:e53339.
33.
NiemanLK, BillerBM, FindlingJW, et al. (2008) The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 93:1526-1540.
34.
OcchiG, Jaffrain-ReaML, TrivellinG, et al. (2010a) The R304X mutation of the aryl hydrocarbon receptor interacting protein gene in familial isolated pituitary adenomas: mutational hot-spot or founder effect?. J Endocrinol Invest, 33:800-805.
35.
OcchiG, TrivellinG, CeccatoF, et al. (2010b) Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia. Eur J Endocrinol, 163:369-376.
36.
PredaV, KorbonitsM, CudlipS, et al. (2014) Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort. Eur J Endocrinol, 171:659-666.
37.
RostomyanL, DalyAF, PetrossiansP, et al. (2015) Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer, 22:745-757.
38.
SchöflC, HoneggerJ, DrosteM, et al. (2014) Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. J Clin Endocrinol Metab, 99:2789-2793.
39.
TichomirowaMA, BarlierA, DalyAF, et al. (2011) High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol, 165:509-515.
40.
VillaC, LagonigroMS, MagriF, et al. (2011) Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Endocr Relat Cancer, 18:347-356.
41.
YarmanS, OgretYD, OguzFS (2015) Do the aryl hydrocarbon receptor interacting protein variants (Q228K and Q307R) play a role in patients with familial and sporadic hormone-secreting pituitary adenomas?. Genet Test Mol Biomarkers, 19:394-398.
42.
YuR, BonertV, SaportaI, et al. (2006) Aryl hydrocarbon receptor interacting protein variants in sporadic pituitary adenomas. J Clin Endocrinol Metab, 91:5126-5129.
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