The number of diseases associated with genetic abnormalities has grown exponentially in the last decade. Pituitary tumours are no exception, as now at least nine genes are known to predispose to pituitary tumour development: MEN1, PRKAR1A, AIP, CDKN1B, SDH (A, B, C and D) and DICER1. On the other hand, only a small minority of the pituitary-related gene carriers develop pituitary disease, suggesting that other interfering genes or factors are also important. Based on our recent assessment in a tertiary referral centre, up to 7% of patients with pituitary adenomas have a family history.
About 20% of familial isolated pituitary adenoma patients have a germline mutation in the AIP gene. These patients have a characteristic phenotype with young-onset, usually somatotroph adenoma which is difficult to control with surgery or medical therapy. We have identified a novel pathway involving somatostatin analogues and AIP: somatostatin analogues increase AIP expression and this, in turn, upregulates the transcription factor ZAC1, known to harbour tumour suppressor activity. This mechanism may explain the poor effect of somatostatin analogues in AIP mutation-positive patients. AIP is a well-conserved gene and its importance is supported by our recent data involving CG1847, the fruitfly orthologue of AIP. Complete CG1847 knockdown leads to lethality but organ-specific knockdown can reveal novel AIP interacting partners.
A seemingly far-fetched link between historical patients suffering from gigantism and current families with childhood-onset acromegaly led to the identification of an AIP mutation which now ties together 17 kindreds with over 80 carriers. Prospective identification of pituitary disease is emerging as a real possibility, which could potentially eradicate the development of gigantism in these families.
Thus, the analysis of genetic syndromes associated with pituitary tumours may shed important light on tumour pathogenesis, and can have a significant impact on patient care.
Declaration of funding
This work was supported by MRC, Wellcome Trust, Barts and the London Charity and Unrestricted educational grant from Pfizer.