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

项目摘要 癌症基因组中的大多数突变是随机乘客，不会导致肿瘤发生，而 只有少数是肿瘤发展的关键驱动因素。现有的癌症疗法直接干扰了 生物学的驱动程序，这已经广泛的特点，在蛋白质编码区，但仍然主要是 在编码区外未表征。大多数肿瘤含有几种驱动突变的组合，但它是 目前尚不清楚肿瘤发展过程中多个事件是如何协调的。申请人的长期目标是 通过确定新的药物靶点和临床标记物来推进癌症医学， 途径。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） 在路径水平上捕获驱动事件的协调，以及（iii）描述非编码驱动对 癌基因表达核心假设是，完善计算的生物学假设， 方法将增强其统计能力。基本原理是，定义非编码驱动程序的生物学， 它们的结合将为新疗法提供坚实的基础。中心假设将在三个测试 具体目标：1）确定将生物机制纳入统计方法的影响， 定位非编码驱动程序; 2）评估启动子突变增加以下表达的机制： 癌症基因;和3）评估肿瘤发展中多个驱动事件的协调。拟议 在申请人看来，研究是创新的，因为它将允许对驾驶员进行无偏见的表征。 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 区域，并促进非计算科学家的统计概念的使用。该提案 重要的是，这将使得能够系统地询问非编码驱动器及其组合。 最终，这将为新的靶向治疗铺平道路。迪特莱因博士将由货车艾伦博士指导， 哈佛医学院医学副教授，在癌症基因组学方面具有丰富的经验 方法，需要统计创新的临床重点问题。他的共同导师迈耶森博士是一位 哈佛医学院遗传学和医学教授，开发靶向疗法的先驱 基于驱动突变。4个计算和2个实验将提供额外的支持 合作者Dietlein博士的培训计划包含四个目标，将通过实践经验来实现 培训、会议和结构化课程：1）获得口译的计算技能 2）通过CRISPR干扰验证驱动突变的实验技术; 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 用于解释癌症基因组中的驱动因子的方法。丹娜-法伯，哈佛医学院和布罗德 学院提供理想的环境来执行申请人的职业发展计划。

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.