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Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic
Thomas Cuny1, Morgane Pertuit, Mona Sahnoun-Fathallah
1Department of Endocrinology, University Hospital of Nancy-Brabois, 54500 Vandoeuvre-les-Nancy, France.
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 (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). 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 (n=3/6) 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.
Insights
Genetic analysis for aryl hydrocarbon receptor interacting protein (AIP) and multiple endocrine neoplasia type 1 (MEN1) mutations is significant in young patients with sporadic pituitary macroadenomas. These mutations, particularly MEN1, are important in prolactinoma cases.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are linked to sporadic pituitary macroadenomas in young patients (≤30 years old).
- Limited data exist on the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in this demographic.
Purpose of the Study:
- To determine the prevalence of AIP and MEN1 genetic abnormalities (mutations and large deletions) in young patients (≤30 years old) with sporadic, isolated pituitary macroadenomas.
- To exclude patients with hypercalcemia or MEN1-associated lesions.
Main Methods:
- Screened entire coding sequences of AIP and MEN1 for mutations in 174 eligible patients across 15 French University Hospital Centers.
- Utilized multiplex ligation-dependent probe amplification (MLPA) for detecting large gene deletions in sequencing-negative cases.
Main Results:
- AIP or MEN1 mutations were found in 12% (21/174) of patients; mutation frequency reached 22% in pediatric patients (≤18 years old).
- Mutations were identified in somatotropinomas (11.3%) and prolactinomas (5.4% each for AIP and MEN1).
- Notably, 33% of non-secreting adenoma patients harbored AIP or MEN1 mutations; no mutations were found in corticotroph or thyrotropinomas.
Conclusions:
- MEN1 mutations are significant in young patients with sporadic, isolated pituitary macroadenomas, especially prolactinomas.
- Combined genetic analysis of AIP and MEN1 is recommended for this patient population.
