Characterizing the load of driver and passenger mutations in cancer

表征癌症中驾驶员和乘客突变的负荷

• 批准号: 8380504
• 负责人: Leonid A Mirny
• 金额: $ 37.46万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380504
• 关键词: Accounting; Achievement; Affect; Antineoplastic Agents; Bioinformatics; Buffers; Cancer Model; Cell Separation; Cells; Cereals; Cessation of life; Complex; Data; Development; Environment; Evolution; Extinction (Psychology); Family; Frequencies; Genes; Genetic; Genetic Load; Genomics; Growth; Heat shock proteins; Heterogeneity; Individual; Late Effects; Lead; Malignant Neoplasms; Measurement; Mediating; Methods; Modeling; Molecular Chaperones; Mutation; Nutrient; Organism; Physics; Plant Roots; Population; Population Genetics; Probability; Process; Proteins; Recording of previous events; Resources; Role; Seminal; Somatic Mutation; Statistical Mechanics; Structure; Study models; Subjects Selections; System; Techniques; Testing; Therapeutic; Time; Work; base; cancer cell; cancer genomics; cancer stem cell; cancer therapy; cell growth; cell transformation; fitness; gain of function mutation; inhibitor/antagonist; mutant; neoplastic; novel strategies; overexpression; research study; sample fixation; simulation; theories; tumor; tumor progression; tumorigenesis

Project 4: Modeling neoplastic progression and analyzing genomic data to characterize the load of driver and passenger mutations in cancer. The development ofcancer can be considered as an evolutionary process within an organism. During neoplastic progression, cells acquire mutations, compete for resources, and are subject of selection for ability to grow fast in a complex and dynamic environment. These processes of Darwinian evolution have been systematically studied and modeled mathematically by methods similar to those used in Statistical Mechanics and related fields of Physics. As a result of somatic micro-evolution a population of cancer cells harbors multiple mutations: a few driver mutations essential for neoplastic progression, and many more passenger mutations. Classical works in population genetics have demonstrated that accumulation of mutations lead to increased genetic load, i.e. reduction in the mean fitness, and can lead to population extinction. Our hypothesis is that increasing the genetic load of mutations present in the population of cancer cells can make the population shrink to extinction, a process that we call clonal extinction. This idea can pave a way to a potentially novel approach to cancer treatment by therapeutics that unleash the deleterious effects of harbored mutations. To the best of our knowledge the idea of exploiting accumulated mutations to push a population of cancer cells into extinction has not been put forward. We propose to test this hypothesis by a unique approach that combines development of a theory of neoplastic evolution, analysis of emerging massive cancer genomics data, and experimental study of passenger mutation and their impact of cancer development. The experiment will reproduce seminal Luria-Delbruck experiment applied to cancer cell. Our data-driven theoretical approach is rooted in fifty years of evolutionary genetic thought about the genetic load and its consequences for population extinction.

项目 4：对肿瘤进展进行建模并分析基因组数据以表征驾驶员和患者的负荷 癌症中的乘客突变。 癌症的发展可以被认为是有机体内的进化过程。期间 肿瘤进展，细胞获得突变，竞争资源，并成为能力选择的对象 在复杂、动态的环境中快速成长。达尔文进化论的这些过程 通过类似于统计力学中使用的方法进行系统的研究和数学建模 以及物理学的相关领域。作为体细胞微进化的结果，癌细胞群体中蕴藏着 多重突变：一些对于肿瘤进展至关重要的驱动突变，以及更多的乘客突变 突变。 群体遗传学的经典研究表明，突变的积累会导致突变的增加。 遗传负荷，即平均适应度的降低，可能导致种群灭绝。我们的假设是 增加癌细胞群体中存在的突变的遗传负荷可以使群体 缩小到灭绝，这个过程我们称之为克隆灭绝。这个想法可以为潜在的小说铺平道路 通过释放所隐藏突变的有害影响的疗法来治疗癌症。至 据我们所知，利用累积的突变将癌细胞群推入 尚未提出灭绝。我们建议通过一种独特的方法来检验这一假设，该方法结合了 肿瘤进化理论的发展，对新兴的大量癌症基因组数据的分析，以及 乘客突变及其对癌症发展影响的实验研究。该实验将 重现应用于癌细胞的开创性 Luria-Delbruck 实验。我们的数据驱动的理论方法是 植根于五十年来关于遗传负荷及其后果的进化遗传学思想 人口灭绝。