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

描述（由申请人提供）：癌症仍然是美国第二大死亡原因。此外，癌症值得注意，因为它主要是一种基因组疾病：大多数肿瘤的出现和持续存在，是因为一系列基因组变化失调了细胞的生长和生存。生殖系变异也可能通过改变药物代谢而增加疾病风险或阻碍癌症治疗选择。癌症基因组信息的变革性医学潜力已经被越来越多的靶向药物所明确，这些药物对具有显著遗传事件的肿瘤显示出显著的疗效，这些肿瘤具有更高的治疗脆弱性。一些突变还能识别出治疗无效甚至有害的肿瘤。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。这些观察结果为一种范式提供了令人信服的理论基础，在这种范式中，所有与治疗相关的肿瘤基因组改变都可能以指导“个性化”治疗的方式呈现给医生。乍一看，翻译癌症基因组用于临床似乎很简单（图1）：(i)通过大规模平行测序来表征基因组；（ii）通过可用药物/靶点纲要筛选这些数据；（iii）向临床专家提供一份带注释的清单。然而，为了实现这一大胆的目标，必须解决多重挑战。首先是技术上的挑战：必须从有限数量的存档肿瘤组织中获得高质量的测序数据。第二是分析方面的挑战：我们必须高精度地识别体细胞和生殖系基因组的变化，并将“驱动”事件与更大范围的“乘客”改变区分开来。第三是临床挑战：我们必须实现“可操作的”数据解释，并制定一个框架，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，还有一个社会心理和伦理挑战：我们必须严格评估患者和肿瘤学家的临床测序经验，并制定原则性方法来应对伴随“临床基因组”时代而来的无数不确定性。我们建议为癌症全外显子组测序的生成、解释和临床实施建立一个健全的框架。为了实现这一目标，我们汇集了来自世界上三个顶级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）、布罗德研究所和布莱根妇女医院（BWH）。该团队将利用DFCI和BWH在个性化癌症医学方面的主要机构合作伙伴关系。经同意后，患者将被纳入肿瘤和正常的临床研究（项目1）

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.