Evaluation of the role of AIP, CDKN1B, miR-107 and AHRR in the pathogenesis of sporadic and familial pituitary adenomas (2011)

Pituitary adenomas are common benign intracranial neoplasms, with the vast majority of such tumours being sporadic. The pathogenesis of sporadic pituitary adenomas remains unclear; however, abnormal microRNAs (miRNAs) expression profiles have been recently associated with these adenomas, suggesting that miRNAs can contribute to tumour formation. In about 5% of cases, pituitary adenomas occur in a familial setting, often as part of multiple endocrine tumours syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex (CNC). Recently, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) and in the CDKN1B (encoding the p27Kip1 protein) genes have been identified as causing pituitary adenoma predisposition (PAP) or associated to the development of multiple endocrine tumours, respectively. Several studies revealed AIP mutations in about 15% of kindreds with familial isolated pituitary adenomas (FIPA), a clinical entity in which pituitary tumours are the sole phenotypic manifestation among family members, while sporadic cases are only rarely mutated. Regarding CDKN1B, so far point mutations have been reported only in few subjects with clinical features of MEN1, including pituitary adenomas, but without MEN1 mutations, suggesting that they rarely cause a MEN-like phenotype in both sporadic and familial MEN1 patients. The aim of the present investigation was to study some of the tumorigenic mechanisms involved in pituitary adenoma formation both in sporadic and familial settings. Genomic DNA of a homogeneous cohort of Italian patients with either sporadic acromegaly or FIPA was analysed for point mutations and gross rearrangements in the AIP and CDKN1B genes. I detected three novel, presumably pathogenic, AIP variants in four apparently sporadic cases, and one known mutation (p.R304X) in a FIPA family. Interestingly, I found that another Italian FIPA family shares the same mutation and haplotype associated with the mutated gene, strongly supporting the presence of a founder effect. No known mutations were found in the CDKN1B gene. The analysis of miR-107, a miRNA involved in the pathogenesis of different types of tumours and predicted to downregulate AIP expression, revealed that it is overexpressed in pituitary adenomas and may act as a tumour suppressor gene. I also provided experimental evidences that AIP-3’UTR is a functional and direct target of miR-107. The study of aryl hydrocarbon receptor repressor (AHRR), a molecule which participates in one of the AIP-related pathways potentially involved in pituitary tumorigenesis, demonstrated an increased expression in GH-secreting adenomas compared to normal pituitaries. In conclusion, the main contribution of this PhD thesis was to provide new knowledge about the pathogenesis of pituitary adenomas. In particular, I found that: - mutations in the AIP and CDKN1B genes seem relatively uncommon in the Italian sporadic acromegalic patients, confirming what already reported in the literature for other populations; - a founder effect for the AIP p.R304X mutation exists in a region of central Italy; - the miRNA miR-107 interacts with AIP and may play roles in pituitary adenoma pathogenesis; - AHRR is overexpressed in somatotropinomas.