Characterisation of novel genetic determinants of Craniopharyngioma tumours

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Adamantinomatous craniopharyngiomas (aCPs) are pituitary tumours which mainly affect children. The pituitary gland is situated at the base of the brain and controls vital body functions such as growth, fertility, metabolism, water balance, stress responses and lactation. The pituitary is controlled by a region of the brain known as the hypothalamus and together they form the hypothalamic-pituitary axis (HP-axis). When the HP-axis is disrupted by aCP tumours, the consequences are devastating and include suboptimal growth, infertility, impaired metabolism, inability of the body to respond to stress, morbid obesity and other hormone disturbances. These tumours can also invade surrounding brain structures causing blindness and impaired intellectual function. As a consequence, these children are in need of lifelong medical care and their development, education and quality of life are severely affected. No drug therapies are available for aCPs and the most common current treatment is a combination of surgery and radiotherapy. Unfortunately, these treatments can have severe side effects due to damage to nearby brain regions. Often, surgeons do not remove the whole tumour to avoid extensive damage to the HP- axis. Additionally, there is a great variability in patient outcome with some patients having a significantly worse prognosis than others despite the same treatment. More personalised treatment will be provided if we can diagnose these tumours more accurately, specifically in terms of their genetic signature. There is an urgent need to understand how these tumours form and to be able to correlate tumour characteristics (molecular signatures) with progression of the disease.We have identified that a large proportion of aCP tumours have a genetic defect (mutation) in a sequence of DNA which encodes a protein known as B-catenin, but these tumours also harbour mutations in other important genes (RNF43, APC and TCFL2) that could have an effect on the disease progression and account for the variable clinical outcomes. However, the role of these genes during early pituitary development and how they lead to tumour formation later in life is not yet known. Understanding the role of these genes and determining if they can predict a patient's clinical outcome would confer an immediate benefit to patients. My overall aim is to understand how these mutated genes (RNF43, APC and TCFL2) either alone or in combination with B-catenin affect tumour development and if there is a correlation between these mutations and the patient's clinical outcomes. In order to achieve this aim I will work on the proposed following objectives:1. To analyse if the mutations in the identified genes RNF43, APC and TCFL2 affect the protein produced and its function within the cell.2. Using animal modelling I will delete the production of proteins by the two most highly mutated genes (RNF43 and APC) to understand their role during pituitary development and tumour formation.3. To investigate if the identified mutations in the genes correlate with the clinical outcomes of the aCP patients. This proposal will advance our knowledge of the development and behaviour of aCPs and will have important clinical implications. We will be able to advise our patients about their prognosis more accurately and tailor their treatment accordingly. For those tumours that confer a better prognosis, less aggressive treatments could be considered, which would spare important brain areas. Successful conservative treatment could lead to less morbidity and mortality and an improved quality of life for children with aCPs.