The Use of Whole-Exome Sequencing to Guide the Care of Cancer Patients

描述(申请人提供)：癌症仍然是美国第二大死因。此外，癌症之所以值得注意，是因为它主要是一种基因组疾病：大多数肿瘤的产生和持续存在是因为一系列基因组变化，这些变化扰乱了细胞的生长和存活。生殖系变异还可能通过改变药物代谢来增加疾病风险或阻碍癌症治疗选择。越来越多的靶向药物对肿瘤显示出显着的疗效，其显著的遗传事件增加了治疗的脆弱性，这清楚地表明了癌症基因组信息的变革性医学潜力。一些突变还可以识别出肿瘤，而治疗是徒劳的，甚至是有害的。许多癌症基因在广泛的肿瘤类型中以不同的频率隐藏着潜在的“可操作的”突变。这些观察结果为一个范例提供了一个令人信服的理由，在这个范例中，所有与治疗相关的肿瘤基因组变化可能会以一种指导“个性化”治疗的方式呈现给医生。乍一看，翻译用于临床的癌症基因组似乎很简单(图1)：(I)通过大规模并行测序来表征基因组；(Ii)通过可用药物/靶标的简编来过滤这些数据；以及(Iii)向专业临床医生提供带注释的列表。然而，必须应对多重挑战，以实现这一大胆的目标。第一个是技术挑战：高质量的测序数据必须从有限数量的档案肿瘤组织中获得。第二个是分析上的挑战：我们必须高精度地识别体细胞和生殖系的基因组变化，并将“驱动”事件与更大的“乘客”改变集区分开来。第三个是临床挑战：我们必须实现“可操作的”数据解释，并开发一个框架，使基因组信息促进基于证据的临床试验和疾病管理选择。最后，还有一个心理社会和伦理挑战：我们必须严格评估患者和肿瘤学家在临床测序方面的经验，并开发有原则的方法来应对伴随着“临床基因组”时代的无数不确定性。我们建议建立一个强大的框架，用于产生、解释和临床实施癌症的整个外显子组测序。为了实现这一目标，我们汇集了来自三个世界顶尖肿瘤学和基因组学研究所的世界级研究人员：达纳-法伯癌症研究所(DFCI)、布罗德研究所和布里格姆妇女医院(BWH)。该团队将利用DFCI和BWH在个性化癌症药物方面已经建立的主要机构合作伙伴关系。同意后，患者将被纳入一项临床研究(项目1)，其中肿瘤和正常 基因组DNA被获取并转移到博德研究所进行整个外显子组测序、分析和解释(项目2)。最终的可操作改变列表将被提供给BWH诊断CLIA实验室进行验证，并返回给项目1临床团队，以便为癌症患者的护理提供信息。CLIA实验室将使用正交法独立查询已知的可操作的突变。同时，我们将对周围不同地点的患者及其肿瘤学家进行纵向调查和定性访谈。 知情同意、数据提供和决策程序(项目3)。完成后，我们将配置一个临床形式主义，通过它，肿瘤学家将基因组信息整合到他们的管理计划中，并将结果报告给癌症患者及其家人。总体倡议将由Levi Garraway博士和Pasi Janne博士共同领导。D.Garraway(项目2 PI)是一位癌症基因组科学家和医学肿瘤学家，他在癌症基因组表征、靶向治疗和个性化癌症医学方面取得了开创性的进展。Janne博士(项目1 PI)是一名转译肿瘤学家，他的重大发现突显了基因组学在抗癌药靶向反应和耐药性中的作用。Steven Joffe博士(Project 3 Pi)在研究伦理方面做出了开创性的贡献，Stacy Gray博士(Project 3 co-Pi)是一位杰出的初级研究员，专注于围绕癌症患者基因测试返回的沟通/政策问题。整个研究团队由翻译肿瘤学、癌症基因组学、临床癌症遗传学、计算生物学、结果研究和研究伦理方面的世界领先者组成。总而言之，这些努力将定义一个可扩展的模型，将临床测序整合到癌症护理中。 与公共卫生相关：在美国导致大多数死亡的疾病中，癌症是一种基因组疾病，值得注意。这种认识正在为癌症护理带来一种新的范式，其中治疗的选择是由每个癌症患者及其肿瘤的基因组中包含的信息来指导的。在这笔赠款中，我们将开发和实施一个强大的框架，用于从“真实世界”的肿瘤材料中生成基因组测序数据，解释出现的大量信息，并将相关基因组信息纳入癌症患者及其家人的护理中。这一努力可能会为临床测序提供一个广泛适用的框架，从而加速个性化癌症药物的到来。

DESCRIPTION (provided by applicant): Cancer remains the second leading cause of death in the United States. Furthermore, cancer is noteworthy because it is primarily a genomic disease: most tumors arise and persist because of a constellation of genomic changes that dysregulate cell growth and survival. Germline variants may also confer increased disease risk or thwart cancer treatment options by altering drug metabolism. The transformative medical potential of cancer genomic information has been made clear by the growing number of targeted agents that show remarkable efficacy against tumors whose salient genetic events confer heightened therapeutic vulnerability. Some mutations also identify tumors for which a therapy will be futile o even harmful. Many cancer genes harbor potentially "actionable" mutations at variable frequencies across a wide range of tumor types. These observations provide a compelling rationale for a paradigm wherein all therapeutically relevant tumor genomic alterations might be presented to physicians in a manner that guides "personalized" treatment. At first blush, translating the cancer genome for clinical use seems straightforward (Figure 1): (i) characterize the genome by massively parallel sequencing; (ii) filter this data through a compendium of available drugs/ targets; and (iii) present an annotated list to expert clinicians. However, multipe challenges must be addressed in order to bring this audacious goal to fruition. The first is a technical challenge: quality sequencing data must be obtained from limiting amounts of archival tumor tissue. The second is an analytical challenge: we must identify somatic and germline genomic changes with high accuracy, and distinguish "driver" events from the much larger set of "passenger" alterations. The third is a clinical challenge: we must achieve "actionable" data interpretation and develop a framework whereby genomic information promotes evidence based clinical trials and disease management choices. Finally, there is a psychosocial and ethical challenge: we must rigorously evaluate patients' and oncologists' experiences of clinical sequencing, and develop principled approaches to confront the myriad uncertainties that accompany the "clinical genome" era. We propose to establish a robust framework for generation, interpretation, and clinical implementation of cancer whole exome sequencing. To accomplish this, we have assembled world-class investigators from three of the world's top institutes for oncology and genomics: the Dana-Farber Cancer Institute (DFCI), the Broad Institute, and the Brigham and Women's Hospital (BWH). This team will leverage a major institutional partnership in personalized cancer medicine already in place at DFCI and BWH. After consent, patients will be enrolled into a clinical study (Project 1) wherein tumor and normal genomic DNA are procured and transferred to the Broad Institute for whole exome sequencing, analysis, and interpretation (Project 2). The resulting list of actionable alterations will be provided to the BWH diagnostic CLIA lab for validation and returned to the Project 1 clinical team to inform the care of cancer patients. The CLIA lab will independently query known actionable mutations using orthogonal approaches. In parallel, we will conduct longitudinal surveys and qualitative interviews of patients and their oncologists at various points surrounding the informed consent, data delivery and decision-making processes (Project 3). Upon completion, we will have configured a clinical formalism through which oncologists incorporate genomic information into their management plan and report the results to cancer patients and their families. The overall initiative will be jointly led by Drs. Levi Garraway and Pasi Janne. D. Garraway (Project 2 PI) is a cancer genome scientist and medical oncologist who has made pioneering advances at the interface of cancer genome characterization, targeted therapeutics, and personalized cancer medicine. Dr. Janne (Project 1 PI) is a translational oncologist who has made major discoveries highlighting the role of genomics in response and resistance to targeted anticancer agents. Dr. Steven Joffe (Project 3 PI) has made seminal contributions pertaining to the ethics of research, and Dr. Stacy Gray (Project 3 co-PI) is an outstanding'junior investigator focusing on communication/policy issues surrounding the return of genetic tests to cancer patients. The overall investigative team consists of world leaders in translational oncology, cancer genomics, clinical cancer genetics, computational biology, outcomes research, and research ethics. Together, these efforts will define a scalable model for the integration of clinical sequencing into cancer care. PUBLIC HEALTH RELEVANCE: Among the diseases that account for most deaths in the United States, cancer is noteworthy for being a disease of the genome. This recognition is bringing forward a new paradigm for cancer care, where the choice of treatment is guided by information contained in the genome of each cancer patient and her tumor. In this grant, we will develop and implement a robust framework for the generation of genome sequencing data from "real-world" tumor materials, interpretation of the vast amounts of information that emerge, and the incorporation of relevant genomic information into the care of cancer patients and their families. This effort may provide a widely applicable framework for clinical sequencing that speeds the advent of personalized cancer medicine.