| dc.description.abstract | Pituitary adenomas (PAs) have a 1:1000 prevalence and carry significant morbidity despite their benign nature. Mutations in the AIP (aryl hydrocarbon receptor interacting protein) gene have been unambiguously associated with higher predisposition for PAs. These tumours pose a challenge in treatment due to delayed diagnosis, increased size, earlier onset, aggressive nature and considerable resistance to therapy. The exact mechanism of the tumour formation due to loss of AIP and the role of AIP in pituitary organogenesis is still unknown. A large-cohort retrospective (225 patients) and prospective (876 patients) clinical study was carried out on the pituitary adenoma patients of a tertiary referral centre in London assessing the prevalence of FIPA (familial isolated pituitary adenomas). 20% of FIPA patients are reported to harbour an AIP mutation, but half of the AIP mutation-positive probands are not aware of a positive family history. This study has shown that active inquiry of family history increases detection of previously unknown family history with nearly 3-fold, enabling the genetic screening of these families for early diagnosis and better customised therapy. The novel, pituitary- specific, biallelic Aip-knockout murine model (AipFlox/Flox; Hesx1Cre/+) generated within this study allowed for the first time to investigate the role of AIP during the embryonic stages. There is phenotypical difference (enlarged anterior lobe, incomplete fusion of the sphenoid bone) in the pituitaries 17.5 dpc AipFlox/Flox; Hesx1Cre/+ embryos when compared with the wildtype of the same embryonic stage, with no difference in cell lineage determination (dpc 15.5). A decrease in growth hormone and prolactin producing cells is described at terminal differentiation (dpc 17.5), which is intriguing because patients harbouring AIP mutations most commonly present with growth hormone and/or prolactin secreting 7 PAs. Further research has since been done efficiently using this model focusing on postnatal tumour formation, which is not part of this thesis. Deregulation of the Hippo signalling components has been increasingly investigated in relation to pituitary tumorigenesis, especially in human hormone secreting PAs, but no study had investigated the role of Hippo signalling in AIP-mediated tumour formation. A bioinformatic-based analysis was performed for the expression of 41 Hippo pathway associated genes in AIP-silenced rat pituitary somatomammotroph GH3 cells, pituitary specific AIP-knockout mice, humans with AIP mutation-positive and AIP mutation-negative familial and sporadic PAs. Both up- and downstream members of the Hippo signalling show significantly altered expression in the different subgroups, which warrants more targeted future studies. Additionally, in the analysed exome and whole genome sequencing of PA patients, variants of several key Hippo pathway components show segregation within families. These data (along with a global phosphorylation analysis) suggest that further studies are needed to investigate the role of Hippo signalling in AIP-mediated tumorigenesis. | en_US |
