Aims: Large genomic deletions have been reported in genes predisposing to endocrine-related cancer syndromes, such as MENI and PRKAR1A. However, this issue had remained unresolved for AlP. Here, we examined whether and to what extent AlP copy number changes account for pituitary adenoma cases previously tested negative for other types of intragenic AlP mutations.
Subjects and Methods: Multiplex Ligation-dependent Probe Amplification (MLPA) assay was performed on blood extracted DNA from 23 familial pituitary adenoma cases, of mostly European origin, as well as from 74 sporadic young pituitary adenoma patients, consisting of 39 Finnish «40 yrs) and 35 Italian pediatric cases. Large genomic deletions were confirmed on genomic and transcript level. Results:Two of21 (9.5%) pituitary adenoma families were found to harbor a germ line AlP deletion: a) A heterozygous -l.5kb deletion, encompassing the in-frame ablation of Exon2, in a British family with clinically non-functioning adenomas and acromegaly; b) A heterozygous -5.8kb deletion, resulting in the ablation of Exons 1 and 2 -including the 5'UTR- in a German family with two acromegaly patients. Both deletions occurred within or in very close proximity to Alu repeatitive elements, suggesting Alu-mediated recombination events. No copy number changes were detected among 67 successfully analyzed sporadic pituitary adenoma patients.
Conclusions: Large genomic AlP deletions account for a subset of familial pituitary adenoma cases. Therefore, in patients undergoing counselling and AlP genetic testing, MLPA should be considered if direct sequencing does not identify a mutation. It is, however, desirable that the detected mutations are further confirmed on genomic DNA or transcript level.
LARGE GENOMIC DELETIONS OF ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN (AlP) GENE CAUSE PITUITARY ADENOMA PREDISPOSITION
1 Department of Medical Genetics, University of Helsinki, Finland, 2Medical Department III, Leipzig University, Germany, 3Clinical Genetics, Great Ormond Street NHS Trust, London, UK, 4Departments of Human Genetics, Oncology and Medicine, McGill University, Montreal, Canada, 5Department of Clinical Genetics, Oulu University Hospital, Finland, 6Department of Endocrinology, Helsinki University Central Hospital, Finland, 7Department of Internal Medicine, General Hospital, Montebelluna, Italy, 8Department of Medicine and Pharmacology, Section of Endocrinology, University of Messina, Italy, 9Division of Endocrinology-Metabolism and Diabetes, Cerrahpa~a Medical Faculty, University of Istanbul, Turkey, 10Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK, 11Department of Clinical Genetics, Guy's Hospital, London, UK, 12Department of Medicine, King's College Hospital, London, UK, 13Department of Endocrinology and Diabetes, London, UK, 14Department of Clinical Genetics, St. Georges, University of London, London, UK, 15Division of Endocrinology, University of Mississippi Medical Center, Jackson, USA
Background: Pituitary adenomas arise sporadically, but -5% occur as components of familial endocrine cancer syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1) and Carney complex (CNC). The genetic background of familial pituitary adenomas, occurring outside the context of MEN1 and CNC, though, had remained elusive. We recently reported that germline mutations in aryl hydrocarbon receptor interacting protein (AlP) gene confer genetic susceptibility to the development of pituitary adenomas, with incomplete penetrancel. These patients are typically diagnosed at young age, mainly with GH-secreting adenomas, without strong family history1.2. Biallelic inactivation and functional evidence suggest a tumor suppressive role for Alpl•3•