Epigenomic Methods to Improve Personalised Treatment in Patients with Lung Cancer and Malignant Pleural Effusion.

肺癌是英国最常见的癌症之一，每年约有3.5万人死于肺癌。大约40%的肺癌患者会出现恶性胸腔积液(MPE)，这是一种积聚在肺和胸壁之间的液体。这种液体的体积可能大到足以压缩肺部，导致呼吸困难。一些患者的MPE体验与其他患者非常不同。例如，有些会存活更长时间，或者会更快地产生液体。人与人之间的这些差异使得预测将会发生什么和选择最好的治疗方法变得极其困难。大多数MPE的治疗依赖于侵入性程序来排出液体，这往往会对患者剩余的生活质量造成重大影响。目前，我们还没有可靠的血液或胸水测试来帮助确定如何最好地处理MPE患者，或者哪些测试可以更好地了解他们会发生什么。每个人的个体DNA模式(他们的基因组)都是他们身体功能的基础。随着时间的推移，或者对某些暴露或疾病的反应，DNA会积累化学变化，影响其遗传信息的解释方式。对这种现象的研究被称为表观遗传学，其中一个关键的变化是DNA甲基化(DNaM)。研究发现，dNaM水平与包括肺癌在内的多种癌症的发生有关。DNaM分析技术正在迅速改进，允许比过去测试更多的基因组。DNaM检测可以应用于胸腔积液，尽管过去的研究通常集中在是否存在癌症上，而不是预测已经患有癌症的人会发生什么。这个项目的目的是评估肺癌患者胸液中的dNaM水平是否可以用来预测他们会发生什么。首先，我们将检查它是否能预测患者可能存活多长时间，但我们也感兴趣的是，它是否能提供关于治疗是否有效的知识，以及MPE的不同行为能否在发生之前被预测。为此，我们将邀请来自布里斯托尔和格拉斯哥的100名肺癌MPE患者参加为期6个月的观察性研究。在研究期间，我们将收集胸水和血液样本，以及关于每个人的疾病正在发生的情况(例如通过CT扫描)以及他们对接受治疗的反应的全面信息，包括癌症和液体。最重要的是，我们将在研究期间跟踪哪些人幸存下来，哪些人没有。然后，我们将把最新的实验室和计算技术应用到我们收集的一些液体样本中，看看dNaM水平是否与研究中患者发生的情况相关。这个项目预计将带来以下好处：1)收集高质量的信息，这将使我们能够设计进一步的结论性研究，以测试胸液dNaM水平是否有助于预测患有MPE的肺癌患者的情况。最终，我们希望创造一种新的、可访问的、基于dNaM的检测方法，它可以应用于从门诊患者那里获得的胸水样本。NHS医生可以常规使用这种测试来预测一个人MPE的可能结果，帮助患者更好地了解他们的疾病，并告知对话如何最好地处理他们的病例。2)收集和存储患者的临床信息和样本，以便进行进一步的测试，这将使我们(以及未来的癌症研究人员)能够应用更多最新的科学技术来预测一个人的MPE随着时间的推移将如何表现。3)更好地了解肺癌和MPE是如何发生和发展的，有可能揭示新的药物疗法的新靶点，并为MPE的研究开辟新的途径。

Lung cancer is one of the most common cancers in the UK, killing around 35,000 people each year. Around 40% of lung cancer patients will develop a malignant pleural effusion (MPE), a collection of fluid which builds up between the lung and the chest wall. The volume of this fluid can be great enough to compress the lung, causing breathlessness. Some patients experience MPE very differently to others. For example, some will survive much longer or will produce fluid much more quickly. These variations between people makes predicting what will happen and choosing the best treatments extremely challenging. Most treatments for MPE rely on invasive procedures to drain the fluid, which often cause a major impact on a patient's remaining quality of life. At present, we have no reliable blood or pleural fluid tests which can help determine how best to manage patients with MPE or which might give a better idea of what will happen to them.Each person's individual DNA pattern (their genome) underpins how their body functions. Over time, or in response to certain exposures or diseases, DNA can accumulate chemical alterations which affect how its genetic information is interpreted. The study of this phenomenon is called epigenetics, with a key alteration being 'DNA methylation' (DNAm). Levels of DNAm have been found to be associated with the development of a wide range of cancers, including lung cancer. DNAm analysis techniques are improving rapidly, allowing more of the genome to be tested than in the past. DNAm testing can be applied to pleural fluid, although past research has usually focused on whether cancer is present or not rather than predicting what will happen to a person who already has cancer. The aim of this project is to assess whether the levels of DNAm in the pleural fluid of a person with lung cancer can be used to forecast what will happen to them. Primarily, we will check whether it can predict how long a patient is likely to survive, but we are also interested in whether it can provide knowledge about whether treatments will work or not and whether the different behaviours of MPE can be predicted before they happen. To do this, we will ask 100 patients with MPE due to lung cancer from Bristol and Glasgow to join an observational study for 6 months. During the study, we will collect pleural fluid and blood samples alongside comprehensive information about what is happening to each person's disease (for example with CT scans) and how they are responding to the treatments they are given, both for the cancer and the fluid. Most importantly, we will track who survives and who does not during the study. We will then apply the latest laboratory and computational techniques to some of the fluid samples we have collected, to see whether the levels of DNAm correlate with what happens to the patients in the study.Benefits from this project are expected to be:1) The gathering of high-quality information which will allow us to design further, conclusive studies to test whether pleural fluid DNAm levels can help to predict what happens to lung cancer patients with MPE. Ultimately, we hope to create a new, accessible, DNAm-based test which can be applied to samples of pleural fluid obtained from patients in outpatient clinics. This test could be used routinely by NHS doctors to predict the likely outcome of a person's MPE, helping patients better understand their disease and informing conversations about how best to manage it in their case. 2) The collection and storage of patients' clinical information and samples with a mind to further testing, which will allow us (and future cancer researchers) to apply more of the most up-to-date scientific techniques to predict how a person's MPE will behave over time. 3) A better understanding of how and why lung cancer and MPE develops and progresses, with the potential to reveal new targets for novel drug therapies and to open up new avenues for MPE research.