PROMINENT - IARC

杰出 - IARC

• 批准号: 10625615
• 负责人: Paul Joseph Brennan
• 金额: $ 39.15万
• 依托单位: INTERNATIONAL AGENCY FOR RES ON CANCER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625615
• 关键词: International Agency for Research on Cancer; Text

The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA, either spontaneous or environmentally induced, are essential for cancer development, recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated, but most of the emphasis has been on the origins of the “driver” mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity, alcohol consumption, inflammation and poor diet in cancer risk, it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA, thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast, recent sequencing studies have uncovered abundant mutations in normal human tissues, suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models, some carried out more than 50 years ago, showing that promotion is the rate-limiting step in tumour development. To identify the mechanisms that control mutated normal cells, and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth, we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology, genetics, computational network analysis and machine learning, tissue imaging of gene expression, single cell transcriptomics, and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries, including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples, together with detailed intervention studies in human populations, mouse models and human organoids, will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations, through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents.

癌症研究界即将在我们对导致人类癌症风险的因素的理解方面取得重大飞跃。虽然很明显，DNA突变，无论是自发的或环境诱导的，是必不可少的癌症的发展，最近的进展突出了非诱变因素的重要性，在人群和小鼠癌症模型中的癌症风险的限速决定因素。 人类癌症的根本原因一直存在广泛的争论，但大多数的重点是在人类肿瘤中普遍存在的“驱动”突变的起源。虽然流行病学研究强调了生活方式因素（如肥胖、饮酒、炎症和不良饮食）在癌症风险中的可能作用，但通常认为这些因素直接或间接导致DNA突变，从而导致肿瘤突变负担并导致癌症风险增加。相比之下，最近的测序研究发现了正常人体组织中的大量突变，这表明即使是强的癌症驱动突变也不足以形成癌症。这些结果是由小鼠肿瘤模型的研究预示的，其中一些是在50多年前进行的，表明促进是肿瘤发展的限速步骤。 为了确定控制突变正常细胞的机制，并阐明促进因子刺激这些细胞转化为肿瘤生长的确切机制，我们组建了一个多学科的研究团队，在流行病学，遗传学，计算网络分析和机器学习，基因表达的组织成像，单细胞转录组学和全基因组CRISPR功能筛选方面具有广泛的经验。我们将集中对来自20多个国家（包括癌症高风险和低风险地区）的数千份人类正常和匹配肿瘤样本进行人体分析。作为Grand Challenge Mutographs研究的一部分，所有这些样本都提供了详细的风险因素信息和全基因组序列数据。对这些样本的分析，以及对人群、小鼠模型和人类类器官的详细干预研究，将使我们能够制定一个从携带驱动突变的单个正常细胞到恶性进展的肿瘤促进路线图。我们的研究结果将有助于识别促进癌症的致病环境因素，并提供新的方法和途径，以预防癌症的基础上，更深入地了解肿瘤促进剂启动细胞选择的过程。