Characterisation of novel genetic determinants of Craniopharyngioma tumours

颅咽管瘤肿瘤新遗传决定因素的表征

• 批准号: MR/S037896/1
• 负责人: James Blackburn
• 金额: $ 43.92万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS037896%2F1
• 关键词: Characterisation; novel; genetic; determinants; Craniopharyngioma

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.

adamantinomatous craniopharyngiomas（aCP）是垂体肿瘤，主要影响儿童。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、水平衡、压力反应和哺乳。脑垂体由大脑中称为下丘脑的区域控制，它们共同形成下丘脑-脑垂体轴（HP轴）。当HP轴被aCP肿瘤破坏时，后果是毁灭性的，包括次优生长、不育、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。这些肿瘤还可以侵入周围的大脑结构，导致失明和智力功能受损。因此，这些儿童需要终身医疗保健，他们的发展、教育和生活质量受到严重影响。没有药物治疗可用于aCP，目前最常见的治疗是手术和放疗的组合。不幸的是，这些治疗可能会由于对附近大脑区域的损伤而产生严重的副作用。通常，外科医生不切除整个肿瘤，以避免对HP轴的广泛损害.此外，患者结局存在很大的差异，尽管治疗相同，但一些患者的预后比其他患者明显更差。如果我们能够更准确地诊断这些肿瘤，特别是在基因特征方面，我们将提供更个性化的治疗。现在迫切需要了解这些肿瘤是如何形成的，并能够将肿瘤特征与我们已经确定大部分aCP肿瘤具有遗传缺陷，这种肿瘤是在编码一种称为B-连环蛋白的蛋白质的DNA序列中发生突变，但这些肿瘤也在其他重要基因中发生突变。在某些情况下，可能对疾病进展有影响并解释可变临床结果的RNF43、APC和TCFL 2。然而，这些基因在早期垂体发育过程中的作用以及它们如何在以后的生活中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为患者带来直接益处。我的总体目标是了解这些突变基因（RNF43，APC和TCFL 2）单独或与B-连环蛋白联合如何影响肿瘤的发展，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，我将努力实现以下目标：1。分析RNF43、APC和TCFL 2基因的突变是否影响蛋白质的产生及其在细胞内的功能.使用动物模型，我将删除两个最高度突变的基因（RNF43和APC）产生的蛋白质，以了解它们在垂体发育和肿瘤形成过程中的作用。研究基因中识别的突变是否与aCP患者的临床结局相关。这一提议将推进我们对aCP的发展和行为的认识，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有关其预后的建议，并相应地调整其治疗。对于那些预后较好的肿瘤，可以考虑采用侵略性较低的治疗方法，这将使重要的大脑区域得以保留。成功的保守治疗可以降低aCP儿童的发病率和死亡率，改善其生活质量。