Characterisation of novel genetic determinants of Craniopharyngioma tumours

成釉细胞性颅咽管瘤(ACPs)是一种主要影响儿童的脑垂体肿瘤。脑下垂体位于大脑的底部，控制着重要的身体功能，如生长、生育、新陈代谢、水分平衡、应激反应和哺乳。脑下垂体由大脑中被称为下丘脑的区域控制，它们共同构成下丘脑-脑垂体轴(HP轴)。当HP轴被ACP肿瘤破坏时，后果是毁灭性的，包括生长不佳、不孕不育、新陈代谢受损、身体无法对压力做出反应、病态肥胖和其他激素紊乱。这些肿瘤还可以侵犯周围的大脑结构，导致失明和智力功能受损。因此，这些儿童需要终身医疗护理，他们的发展、教育和生活质量受到严重影响。ACPs目前尚无药物治疗方法，目前最常见的治疗方法是手术和放射治疗相结合。不幸的是，这些治疗方法可能会对附近的大脑区域造成严重的副作用。通常，外科医生不会为了避免对HP轴造成广泛损害而切除整个肿瘤。此外，患者的预后有很大的差异，尽管接受了相同的治疗，但一些患者的预后明显比其他患者差。如果我们能更准确地诊断这些肿瘤，特别是根据它们的基因特征，将提供更个性化的治疗。迫切需要了解这些肿瘤是如何形成的，并能够将肿瘤特征(分子特征)与疾病的进展联系起来。我们已经发现，很大比例的ACP肿瘤在编码B-连环蛋白的DNA序列中存在遗传缺陷(突变)，但这些肿瘤还存在其他重要基因(RNF43、APC和TCFL2)的突变，这些基因可能对疾病进展产生影响，并解释了不同的临床结果。然而，这些基因在早期脑垂体发育中的作用以及它们如何在生命后期导致肿瘤形成尚不清楚。了解这些基因的作用并确定它们是否可以预测患者的临床结果将立即为患者带来好处。我的总体目标是了解这些突变基因(RNF43、APC和TCFL2)是如何单独或与B-连环蛋白一起影响肿瘤发展的，以及这些突变与患者的临床结果之间是否存在相关性。为了实现这一目标，我将致力于拟议的以下目标：1.分析已识别的基因RNF43、APC和TCFL2的突变是否会影响蛋白质的产生及其在细胞内的功能。利用动物模型，我将删除两个高度突变的基因(RNF43和APC)产生的蛋白质，以了解它们在脑垂体发育和肿瘤形成中的作用。研究已发现的基因突变是否与ACP患者的临床结果相关。这一建议将促进我们对ACP的发展和行为的了解，并将具有重要的临床意义。我们将能够更准确地向患者提供他们的预后建议，并相应地为他们量身定做治疗方案。对于那些预后较好的肿瘤，可以考虑不那么激进的治疗方法，这将节省重要的大脑区域。成功的保守治疗可以降低急性冠脉综合征的发病率和死亡率，提高儿童的生活质量。

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.