Genetic predisposition and functional analysis of pituitary adenomas

Abstract

Pituitary adenomas are the most common type of intracranial tumours and albeit being mostly benign, represent a significant burden both on patient quality of life and the public health system. This thesis aimed at investigating various molecular aspects of this disease, including genetic susceptibility, molecular mechanisms of tumorigenesis, and the cellular physiology of octreotide treatment. A novel mis-sense mutation, R9Q, was identified in a local acromegalic patient in the aryl hydrocarbon receptor-interaction protein (AlP), a tumour suppressor gene commonly altered in familial cases of pituitary adenomas. The R9Q AlP mutant was shown to lose the ability to hinder proliferation successfully in primary pituitary cells and cell lines when compared to the wild-type but the functional consequence of this mutation remains speculative. The truncating R304X mutant lacked complete function compared to wild-type. This study was the first to propose a functional mechanism for the protective role of AlP. Wild-type AlP was demonstrated to reduce forskolin-induced cAMP levels and downstream cAMP response element (CRE) - driven transcription, resulting in a respective reduction in growth h011110ne secretion from GH3 cells. This reduction occurred independently of phosphodiesterase activity. Over-expression of wild-type AlP also reduced MYC oncogene expression, proposing another possible mechanism for AlP's tumour suppressive ability. Immunohistochemical analysis of Wnt proteins in 47 local tumours revealed that Wnt pathway activation occurs independently of β-catenin transcription factor and that MYC and Cyelin D 1 oncoproteins play a significant role in the initiation and progression of the disease respectively. A novel gender difference in Cyelin D 1 expression was noted. MYC protein expression was not correlated with tumour recurrence and evidence from octreotide treatment 111 patients and in GH3 cells, together with significantly lower MYC expression in patients with hypopituitarism, lends evidence for the honnonally controlled expression of the MYC gene. Surviving oncoprotein expression was extremely low, both in local tumours and GH3 cells, indicating at best a minor role in pituitary tumorigenesis