A pan-cancer atlas of driver mutations in >100,000 patients based on a hypothesis-driven combined computational and experimental approach

项目总结 癌症基因组中的大多数突变都是随机乘客，不会导致肿瘤发生，而 只有少数几个是肿瘤发展的关键驱动因素。现有的癌症治疗方法直接干扰了 驱动因素的生物学，在蛋白质编码区被广泛描述，但在很大程度上仍然存在 编码区外未特化。大多数肿瘤都含有几种驱动基因突变的组合，但它是 不清楚多个事件在肿瘤发展中是如何协调的。申请者的长期目标是 为复杂疾病的治疗寻找新的药物靶点和临床标记物，推动癌症医学的发展 小路。本申请的总体目标是(I)揭示非编码驱动程序的生物学作用，(Ii) 捕获路径级别的驱动程序事件的协调，以及(Iii)描述非编码驱动程序对 癌症基因的表达。中心假设是精炼计算的生物学假设 方法将增强他们的统计能力。其基本原理是定义非编码驱动程序的生物学和 它们的结合将为新疗法提供坚实的基础。核心假说将在三年内得到检验 具体目标：1)确定将生物机制纳入统计方法的影响 定位非编码驱动因素；2)评估启动子突变增加其表达的机制 癌症基因；以及3)评估肿瘤发展中多个驱动事件的协调。建议数 申请人认为，研究是创新的，因为它将允许对司机进行公正的描述 跨整个基因组的突变，解决了现有癌症基因组学方法在非编码方面的局限性 区域，并为非计算型科学家使用统计概念提供便利。该提案是 意义重大，因为它将实现对非编码驱动程序及其组合的系统询问。 最终，这将为新的靶向疗法铺平道路。Dietlein博士将由Van Allen博士指导，他是 哈佛医学院医学副教授，在癌症基因组学方面有丰富经验 需要对临床重点问题进行统计创新的方法。他的合作导师迈耶森博士是一位 哈佛医学院遗传学和医学教授，靶向治疗的先驱 基于司机的突变。额外的支持将由4名计算人员和2名实验人员提供 合作者。Dietlein博士的培训计划包含四个目标，这些目标将通过亲身体验来实现 培训、会议和有组织的课程：1)掌握口译的计算技能 非编码区的驱动程序；2)通过CRISPR干扰验证驱动程序突变的实验技术； 3)培养跨学科科学家团队的专业领导技能；4)使用机器学习 解释癌症基因组中的驱动因素的方法。Dana-Farber，哈佛医学院和博大 学院为执行申请人的职业发展计划提供了理想的环境。

PROJECT SUMMARY Most mutations in cancer genomes are random passengers that do not contribute to oncogenesis, whereas only a few are drivers critical for tumor development. Existing cancer therapies interfere directly with the biology of drivers, which have been characterized extensively in protein-coding regions but remain largely uncharacterized outside coding regions. Most tumors harbor a combination of several driver mutations, but it is unclear how multiple events are coordinated in tumor development. The applicant's long-term goal is to advance cancer medicine by identifying new drug targets and clinical markers for therapies in complex pathways. The overall objectives in this application are to (i) reveal the biological role of noncoding drivers, (ii) capture the coordination of driver events at a pathway level, and (iii) profile the effects of noncoding drivers on cancer gene expression. The central hypothesis is that refining the biological assumptions of computational methods will enhance their statistical power. The rationale is that defining the biology of noncoding drivers and their combination will offer a strong foundation for new therapies. The central hypothesis will be tested in three specific aims: 1) Determine the impact of integrating biological mechanisms into statistical methods for localizing noncoding drivers; 2) Evaluate mechanisms by which promoter mutations increase the expression of cancer genes; and 3) Assess the coordination of multiple driver events in tumor development. The proposed research is innovative, in the applicant's opinion, because it will allow for an unbiased characterization of driver mutations across the entire genome, address the limitations of existing cancer genomics methods in noncoding regions, and facilitate the usage of statistical concepts for non-computational scientists. The proposal is significant because it will enable a systematic interrogation of noncoding drivers and their combinations. Ultimately, this will pave the way for new targeted therapies. Dr. Dietlein will be mentored by Dr. Van Allen, an Associate Professor of Medicine at Harvard Medical School with considerable experience in cancer genomics methods that require statistical innovation for clinically focused questions. His co-mentor, Dr. Meyerson, is a Professor of Genetics and Medicine at Harvard Medical School and a pioneer in developing targeted therapies based on driver mutations. Additional support will be provided by 4 computational and 2 experimental collaborators. Dr. Dietlein's training plan contains four goals, which will be pursued by hands-on experiential training, conference meetings, and structured coursework: 1) Acquire computational skills for interpreting drivers in noncoding regions; 2) Experimental techniques to validate driver mutations by CRISPR interference; 3) Develop professional leadership skills for interdisciplinary teams of scientists; and 4) Use machine-learning methods for interpreting drivers in cancer genomes. Dana-Farber, Harvard Medical School, and the Broad Institute provide an ideal environment to execute the applicant's career development plan.