Germline AIP Mutations in Apparently Sporadic Pituitary Adenomas: Prevalence in a Prospective Single-Center Cohort of 443 Patients

Cazabat, Laure; Bouligand, Jérôme; Salenave, Sylvie; Bernier, Michèle; Gaillard, Stéphan; Parker, Fabrice; Young, Jacques; Guiochon‐Mantel, Anne; Chanson, Philippe

doi:10.1210/jc.2011-2291

Cited by 163 publications

(148 citation statements)

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“…A long prospective study is clearly required to assess the impact of AIP screening in family members of AIPmut patients in order to clarify the natural history of asymptomatic AIPmut carriers. In mutation-negative patients, we did not identify any large genomic deletion of AIP by MLPA in agreement with three other previous studies (6,7,11). This molecular abnormality could account for 9.5% of AIPnegative FIPA kindreds (30), and among 64 unrelated patients from a FIPA cohort of our laboratory, we identified one family member of homogenous FIPA with acromegaly, with large genomic deletion of AIP in exon 1 (A Barlier, personal communication).…”

Section: Marker Genomic Positionsupporting

confidence: 92%

“…Indeed, in our study, the positive genetic screening in the three family members was not accompanied by the identification of any PA on MRI. In five AIPmut carriers from the study of Cazabat et al (7), no adenoma was identified by MRI, and of the AIPmut carriers (nZ2/21) from the study conducted by Tichomirowa et al (11), two family members (not included in the current study) were diagnosed with a microadenoma and without associated hormonal oversecretion. Whether there are specific AIP mutants associated with higher penetrance of the disease (34) and (35).…”

Section: Marker Genomic Positionmentioning

confidence: 72%

“…Bold represents the more likely at-risk haplotype shared by at least two subjects. near 7% (7,8). This prevalence reaches 14.3% in patients with GH-secreting tumors diagnosed before 25 years old (28).…”

Section: Discussionmentioning

confidence: 92%

“…No mutation was found in corticotroph adenoma patients and in the single thyrotropinoma patient. However, AIP mutations have already been reported in several young patients with isolated sporadic corticotroph adenomas (7,21), justifying AIP screening in such populations (Fig. 1).…”

Section: Marker Genomic Positionmentioning

confidence: 95%

“…In 2006, Vierimaa et al (4) identified mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in the familial setting of PA. In FIPA kindreds, AIP mutations occur in 15-20% of cases (5), whereas they occur at a very low frequency in sporadic cases, between 0 and 4% (6,7,8,9). Because patients mutated for AIP (AIPmut) have typically early onset disease and larger PA compared with controls (10), Tichomirowa et al (11) performed AIP screening in young patients with isolated sporadic macroadenomas and identified that nearly 12% of patients had germline AIP mutations.…”

Section: Introductionmentioning

confidence: 99%

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Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

Cuny

Pertuit

Sahnoun-Fathallah

et al. 2013

European Journal of Endocrinology

151

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Context: Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age %30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. Objective: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age %30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. Design: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. Patients and settings: One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. Results: Twenty-one out of 174 (12%) patients had AIP (nZ15, 8.6%) or MEN1 (nZ6, 3.4%) mutations. In pediatric patients (age %18 years old), AIP/MEN1 mutation frequency reached nearly 22% (nZ10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (nZ3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. Conclusion: Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

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Section: Marker Genomic Positionsupporting

confidence: 92%

Section: Marker Genomic Positionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 92%

Section: Marker Genomic Positionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

Cuny

Pertuit

Sahnoun-Fathallah

et al. 2013

European Journal of Endocrinology

151

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The Molecular Genetics of Corticotroph Tumours

Dworakowska

Grossman

2014

Encyclopedia of Life Sciences

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Cushing disease caused by adrenocorticotropin ‐secreting pituitary adenomas leads to hypercortisolaemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity and increased mortality. Previous studies have enhanced our knowledge on the genetic basis of familial pituitary adenomas, including the McCune–Albright syndrome, multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), Carney complex, the MEN1‐like phenotype (MEN4), pituitary adenoma predisposition syndromes and tuberous sclerosis. These studies, however, have done little to elucidate the causes of sporadic pituitary tumours, including Cushing disease. We summarise the information available on the molecular derangements of corticotroph tumours, including the most recent advances in the molecular genetics of sporadic lesions, which were published after the latest review on this topic written in 2011. We have left for further reading information about silent corticotroph adenomas, as well as plurihormonal expressing adenomas. We also suggest that more general literature for the readers who want to broaden their knowledge on the molecular biology in general of pituitary adrenomas. Key Concepts: Some 5% of pituitary adenomas are familial. Previous studies have enhanced our knowledge on the genetic basis of familial pituitary adenomas including the McCune–Albright syndrome (MAS), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), Carney complex (CNC), the MEN1‐like phenotype (MEN4), pituitary adenoma predisposition (PAP) syndromes and tuberous sclerosis (TSC). These studies, however, have done little to elucidate the causes of sporadic pituitary tumours, including Cushing disease. Molecular studies on pituitary tumours have shown that alterations in the best known tumour suppressor genes in other neoplasms (e.g. P53 , RB , etc.) or common oncogenes (e.g. the Ras ‐familly) are only rarely involved in the development of these tumours. Silent corticotroph adenomas (SCA) are rare pituitary tumours that are immunoreactive for ACTH, but without clinical evidence of Cushing disease, and tend to show aggressive features. Future work should focus on understanding the molecular mechanisms that control pituitary tumour transformation, where intracellular signalling molecules will constitute not only diagnostic/prognostic markers but also novel therapeutic targets.

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Familial Pituitary Adenomas

Hernández-Ramírez

Korbonits

2013

Pituitary Disorders

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Germline AIP Mutations in Apparently Sporadic Pituitary Adenomas: Prevalence in a Prospective Single-Center Cohort of 443 Patients

Cited by 163 publications

References 21 publications

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

The Molecular Genetics of Corticotroph Tumours

Familial Pituitary Adenomas

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