Title of project

Genetic determinants of pituitary tumours

Abstract

Pituitary tumours can cause severe life-long disease, especially in familial and childhood-onset cases, but earlier diagnosis would allow for treatment sooner, thus minimising suffering. Among patients with isolated pituitary adenomas, the majority has sporadic disease with a minority having often low penetrance familial disease, with known mutations in 10% of cases. Data from families, either with known mutations in the AIP or MEN1 genes, or with mutations in currently unknown genes, suggest that not all family members carrying a DNA change develop pituitary tumours, representing incomplete penetrance. We believe that there is genetic predisposition for the development of sporadic and gene negative cases, and these would also influence penetrance in monogenic conditions. Our two main questions are:

• What are the genetic changes that predispose to sporadic pituitary tumours?
• What genetic factors lead to development of a tumour in patients with monogenic forms of low penetrance familial pituitary diseases?

A long-standing collaboration has existed with between our two research groups (Dr Jakob Dal and Prof Marta Korbonits), which has led to several publications (1,2) with an additional new manuscript recently submitted, and further data within the FIPA consortium (3,4). The Department of Endocrinology at Aalborg University has a unique cohort of well-defined and representative individuals with known pituitary disorders collected through current or upcoming PhD projects. This includes conditions such as acromegaly, prolactinomas, and large non-hormone-producing tumours (NFPA). Genetic data for these patients could be crucial in answering these important research questions. By setting up a polygenic risk score and identifying multiple genetic markers which could contribute to disease predisposition via a large internation genome wide association study. We will then also apply the polygenic risk score to monogenic disease mutation carriers (affected or not affected) to predict disease penetrance.

Aim of the visit is

• Strengthen our collaboration and increasing the training of local endocrinologist regarding pituitary adenoma genetics and pituitary adenoma research in general
• Identify pituitary adenoma kindreds with germline mutations predisposing to pituitary adenoma
• To set up a study to collect DNA for a genome wide association study