Mapping tumour molecular mechanisms associated with common exposures: a new approach to identifying targets to prevent and treat cancer

绘制与常见暴露相关的肿瘤分子机制：确定预防和治疗癌症靶标的新方法

• 批准号: MR/T043202/2
• 负责人: Siddhartha Kar
• 金额: $ 51.67万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT043202%2F2
• 关键词: Mapping; tumour; molecular; mechanisms; associated

Every year, over 360,000 people in the UK are diagnosed with cancer and around 160,000 die as a result of the disease. Cancer costs the NHS over £5 billion annually, while the loss of human productivity due to cancer in the UK is estimated to be £18 billion a year. Above all, cancer impacts patients and their families in ways that are beyond measure. This makes cancer one of the most pressing societal challenges of this century.Cancer is a disease of the genome. Certain changes that are acquired over the course of life in the genomes of healthy cells in the human body (somatic genomic changes) dysregulate the fine balance between cell death and proliferation. These somatic genomic aberrations are the cornerstone of malignant cellular transformation. Targeting somatic genomic changes is fundamental to the practice of precision cancer medicine. We understand that common exposures and cancer risk factors such as ultraviolet light and smoking accelerate the acquisition of these changes. However, little is actually known about how everyday exogeneous and endogenous factors such as diet, obesity, and insulin resistance relate to, and likely drive, carcinogenic changes in the somatic genome. This is because it is difficult to measure lifelong trajectories of the factors retrospectively at cancer diagnosis and expensive to measure them prospectively in large numbers of individuals until some of them develop cancer. Such one-time "snapshot" measures, even where feasible, are prone to bias and confounding. Specific inherited or germline genetic variants have been found to be robustly associated with these exposures or factors. Since genetic variants are allocated at random at conception and fixed thereafter, they are less affected by bias and confounding. The factor-associated variants provide remarkable proxies for the lifetime levels of these factors even in patients in whom the factor itself has not been measured. These variants collected into polygenic scores serve as instruments in Mendelian randomisation (MR) studies that evaluate association between the germline genetically-inferred levels of the factor and a disease outcome. MR studies of cancer have so far been limited to an appraisal of the relationship between putative risk factors and cancer risk.The crucial conceptual advances being proposed here are the application of an MR-like approach to identify somatic/tumour molecular changes that operate within the cancer and are associated with factors such as obesity and the illumination of the role of the identified tumour molecular changes in driving cancer progression and response to cancer drugs. This novel shift in the conventional MR paradigm is challenging to accomplish but has dramatic potential for translational clinical impact. First, by testing for association between a comprehensive range of potentially modifiable everyday exposures and specific somatic genetic mechanisms on the pathway to cancer, the proposed research will generate a rich catalogue of precise molecular targets for further preventive intervention. The availability of a target would mean that such intervention could go beyond policies aimed at influencing behaviour and take the form of primary chemoprevention for high-risk populations. Second, these molecular targets with a clear and well-reasoned link to common exposures may serve as biomarkers for early detection and in the diagnostic or prognostic classification of cancer. Third, untangling the complex interplay between extrinsic/intrinsic exposures and the somatic genome and establishing the sequence of events from exposure to pre-malignancy to cancer may inform strategies for rational anti-tumour therapeutic development. An exhaustive set of tumour molecular changes will be evaluated but a particular focus will be on mutational signatures and anti-tumour immune cell infiltrate signatures, given that these may determine response to chemotherapy, and targeted and immuno-oncology treatments.

英国每年有超过 360,000 人被诊断患有癌症，约 160,000 人死于该疾病。癌症每年给 NHS 造成超过 50 亿英镑的损失，而英国每年因癌症造成的人类生产力损失估计为 180 亿英镑。最重要的是，癌症对患者及其家人的影响是无法估量的。这使得癌症成为本世纪最紧迫的社会挑战之一。癌症是一种基因组疾病。人体内健康细胞的基因组在生命过程中发生的某些变化（体细胞基因组变化）会失调细胞死亡和增殖之间的良好平衡。这些体细胞基因组畸变是恶性细胞转化的基石。针对体细胞基因组变化是精准癌症医学实践的基础。我们知道，常见的暴露和癌症危险因素（例如紫外线和吸烟）会加速这些变化的发生。然而，人们实际上对饮食、肥胖和胰岛素抵抗等日常外源性和内源性因素如何与体细胞基因组的致癌变化相关并可能驱动其发生作用知之甚少。这是因为在癌症诊断时很难回顾性地测量这些因素的终生轨迹，而且在大量个体中前瞻性地测量它们的成本很高，直到其中一些人患上癌症。这种一次性“快照”措施，即使在可行的情况下，也容易产生偏见和混淆。已发现特定的遗传或种系遗传变异与这些暴露或因素密切相关。由于遗传变异在受孕时随机分配并随后固定，因此受偏差和混杂因素的影响较小。即使在因子本身尚未测量的患者中，因子相关变异也为这些因子的终生水平提供了显着的代理。这些收集到多基因评分中的变异可作为孟德尔随机化 (MR) 研究的工具，用于评估该因子的种系遗传推断水平与疾病结果之间的关联。迄今为止，癌症的 MR 研究仅限于评估假定的风险因素和癌症风险之间的关系。这里提出的关键概念进展是应用类似 MR 的方法来识别癌症内起作用的体细胞/肿瘤分子变化，并与肥胖等因素相关，并阐明所识别的肿瘤分子变化在驱动癌症进展和对癌症药物的反应中的作用。传统 MR 范式的这种新颖转变很难实现，但具有转化临床影响的巨大潜力。首先，通过测试一系列潜在可改变的日常暴露与癌症途径中特定体细胞遗传机制之间的关联，拟议的研究将产生丰富的精确分子靶标目录，以供进一步的预防干预。目标的可用性意味着这种干预措施可以超越旨在影响行为的政策，并采取针对高危人群的初级化学预防的形式。其次，这些与常见暴露有明确且合理的联系的分子靶点可以作为早期检测以及癌症诊断或预后分类的生物标志物。第三，理清外在/内在暴露与体细胞基因组之间复杂的相互作用，并建立从暴露到癌前病变到癌症的事件顺序，可以为合理的抗肿瘤治疗开发策略提供信息。将评估一系列详尽的肿瘤分子变化，但特别关注突变特征和抗肿瘤免疫细胞浸润特征，因为这些可能决定对化疗、靶向和免疫肿瘤治疗的反应。