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

每年，英国有超过36万人被诊断患有癌症，约16万人死于癌症。癌症每年花费NHS超过50亿英镑，而英国因癌症造成的人类生产力损失估计为每年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。人体健康细胞基因组在生命过程中获得的某些变化（体细胞基因组变化）会破坏细胞死亡与增殖之间的微妙平衡。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确癌症医学实践的基础。我们知道，常见的暴露和癌症风险因素，如紫外线和吸烟，会加速这些变化的发生。然而，对于日常的外源性和内源性因素，如饮食、肥胖和胰岛素抵抗，如何与体细胞基因组的致癌变化相关，以及可能驱动这些因素，我们知之甚少。这是因为在癌症诊断时回顾性地测量这些因素的终生轨迹是困难的，而在大量个体中进行前瞻性的测量是昂贵的，直到其中一些人患上癌症。这种一次性的“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是随机分配的，之后是固定的，因此受偏差和混淆的影响较小。这些因素相关的变异为这些因素的终生水平提供了显著的代用物，即使在这些因素本身没有被测量的患者中也是如此。收集到多基因评分中的这些变异作为孟德尔随机化（MR）研究的工具，用于评估生殖系遗传推断的因子水平与疾病结果之间的关联。到目前为止，对癌症的核磁共振研究仅限于评估假定的危险因素与癌症风险之间的关系。这里提出的关键概念进展是应用核磁共振样方法来识别在癌症中运作的与肥胖等因素相关的体细胞/肿瘤分子变化，以及阐明已识别的肿瘤分子变化在驱动癌症进展和对癌症药物反应中的作用。这一传统磁共振范式的新转变具有挑战性，但具有巨大的转化临床影响潜力。首先，通过测试广泛的潜在可改变的日常暴露与癌症途径上特定的体细胞遗传机制之间的关联，拟议的研究将为进一步的预防干预产生丰富的精确分子靶点目录。如果有一个目标，就意味着这种干预可以超越旨在影响行为的政策，并采取对高危人群进行初级化学预防的形式。其次，这些分子靶点与常见暴露有明确和合理的联系，可以作为早期检测和癌症诊断或预后分类的生物标志物。第三，解开外在/内在暴露与体细胞基因组之间复杂的相互作用，并建立从暴露到恶性肿瘤前到癌症的事件序列，可能为合理的抗肿瘤治疗开发提供策略。一组详尽的肿瘤分子变化将被评估，但特别关注的是突变特征和抗肿瘤免疫细胞浸润特征，因为这些特征可能决定对化疗、靶向和免疫肿瘤治疗的反应。

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.