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/T043202/1
• 负责人: Siddhartha Kar
• 金额: $ 104.24万
• 依托单位: University of Bristol
• 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%2FT043202%2F1
• 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.

在英国，每年有超过36万人被诊断出患有癌症，其中约16万人死于癌症。癌症每年给NHS造成的损失超过50亿GB，而在英国，癌症每年造成的人类生产力损失估计为180亿GB。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)破坏了细胞死亡和增殖之间的微妙平衡。这些体细胞基因组的异常是恶性细胞转化的基石。以体细胞基因组变化为靶点是精确癌症医学实践的基础。我们理解，常见的暴露和癌症风险因素，如紫外线和吸烟，加速了这些变化的获得。然而，关于饮食、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中的致癌变化相关并可能推动这些变化，人们实际上知之甚少。这是因为在癌症诊断时很难回溯地测量这些因素的终身轨迹，而且在大量个体中前瞻性地测量它们，直到其中一些人患上癌症，成本高昂。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生殖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，因此它们受到偏见和混淆的影响较小。因子相关变异体提供了这些因子终生水平的显着替代，即使在因子本身未被测量的患者中也是如此。这些被收集到多基因评分中的变异被用作孟德尔随机化(MR)研究的工具，该研究评估该因子的种系遗传推断水平与疾病结果之间的关联。到目前为止，对癌症的MR研究仅限于对假定的风险因素和癌症风险之间的关系进行评估。这里提出的关键概念进展是应用类似MR的方法来识别在癌症中运作的体细胞/肿瘤分子变化，以及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推动癌症进展和抗癌药物反应中的作用。这一传统磁共振范式的新转变具有挑战性，但具有翻译性临床影响的巨大潜力。首先，通过测试一系列潜在的可改变的日常暴露与致癌途径上特定的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，用于进一步的预防干预。目标的存在将意味着这种干预可以超越旨在影响行为的政策，而采取针对高危人群的主要化学预防的形式。其次，这些分子靶标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记物。第三，解开外在/内在暴露和体细胞基因组之间的复杂相互作用，并建立从暴露到癌症前期到癌症的事件序列，可能会为合理的抗肿瘤治疗开发提供策略。将对一套详尽的肿瘤分子变化进行评估，但特别关注突变特征和抗肿瘤免疫细胞浸润性特征，因为这些特征可能决定对化疗以及靶向和免疫肿瘤治疗的反应。

项目成果

A New Frontier for Cancer Genetics: Identification of Germline-Somatic Associations.

癌症遗传学的新前沿：种系-体细胞关联的鉴定。

• DOI: 10.1158/0008-5472.can-23-0152
• 发表时间: 2023
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Kar SP

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

• DOI: 10.1093/jnci/djac087
• 发表时间: 2022-08-08
• 期刊: Journal of the National Cancer Institute

Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.

• DOI: 10.1371/journal.pgen.1009887
• 发表时间: 2022-01
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Hayes BL;Robinson T;Kar S;Ruth KS;Tsilidis KK;Frayling T;Murray A;Martin RM;Lawlor DA;Richmond RC
• 通讯作者: Richmond RC

Child and adult adiposity and subtype-specific endometrial cancer risk: a multivariable Mendelian randomisation study.

• DOI: 10.1038/s41366-022-01231-y
• 发表时间: 2023-01
• 期刊: International journal of obesity (2005)
• 作者: Kennedy OJ;Bafligil C;O'Mara TA;Wang X;Evans DG;Kar S;Crosbie EJ
• 通讯作者: Crosbie EJ

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

• DOI: 10.1038/s41588-022-01121-z
• 发表时间: 2022-08
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Kar, Siddhartha P.;Quiros, Pedro M.;Gu, Muxin;Jiang, Tao;Mitchell, Jonathan;Langdon, Ryan;Iyer, Vivek;Barcena, Clea;Vijayabaskar, M. S.;Fabre, Margarete A.;Carter, Paul;Petrovski, Slave;Burgess, Stephen;Vassiliou, George S.
• 通讯作者: Vassiliou, George S.