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

使用全外显子组测序指导癌症患者的护理

• 批准号: 8582557
• 负责人: Levi A. Garraway
• 金额: $ 147.02万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582557
• 关键词: Accounting; Address; Antineoplastic Agents; Blushing; Cancer Patient; Caring; Cause of Death; Cell Survival; Cessation of life; Clinical; Clinical Research; Clinical Trials; Communication; Computational Biology; Consent; Dana-Farber Cancer Institute; Data; Decision Making; Diagnostic; Disease; Disease Management; Drug Targeting; Enrollment; Ethics; Event; Family; Frequencies; Generations; Genetic; Genetic screening method; Genome; Genomic DNA; Genomics; Goals; Grant; Gray unit of radiation dose; Hospitals; Informed Consent; Institutes; Interview; Longitudinal Surveys; Malignant Neoplasms; Massive Parallel Sequencing; Medical; Medical Oncologist; Medicine; Modeling; Mutation; Oncogenes; Oncologist; Outcomes Research; Patients; Physicians; Policies; Process; Reporting; Research Ethics; Research Personnel; Resistance; Role; Scientist; Seminal; Sequence Analysis; Speed; Therapeutic; Translating; Tumor Tissue; Uncertainty; United States; Validation; Variant; Woman; cancer care; cancer genetics; cancer genome; cancer genomics; cancer therapy; cell growth; disorder risk; drug metabolism; evidence base; exome sequencing; experience; genome sequencing; oncology; psychosocial; response; therapeutic target; tumor

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.

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是因为一系列基因组变化导致细胞生长和生存失调。生殖系变异也可能通过改变药物代谢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通过越来越多的靶向药物而变得清晰，这些药物对肿瘤显示出显著的疗效，而肿瘤的显著遗传事件赋予了更高的治疗脆弱性。一些突变还可以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可变的频率存在潜在的“可操作”突变。这些观察结果提供了一个令人信服的理论基础的范例，其中所有治疗相关的肿瘤基因组改变可能会提交给医生的方式，指导“个性化”治疗。 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表征基因组;（ii）通过可用药物/靶标的概要过滤这些数据;（iii）向临床专家提供注释列表。然而，为了实现这一大胆的目标，必须应对多重挑战。首先是技术挑战：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。第二个是分析上的挑战：我们必须以高精度识别体细胞和生殖细胞基因组的变化，并将“驱动”事件与更大的“乘客”改变区分开来。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，并制定原则性的方法来应对伴随“临床基因组”时代而来的无数不确定性。 我们建议建立一个强大的框架，用于生成，解释和临床实施癌症全外显子组测序。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：丹娜-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已经在个性化癌症医学方面的主要机构合作伙伴关系。在同意后，患者将被招募到临床研究（项目1）中，其中肿瘤和正常对照组的肿瘤。 获取基因组DNA并转移到布罗德研究所进行全外显子组测序、分析和解释（项目2）。可采取行动的改变的结果列表将提供给BWH诊断CLIA实验室进行验证，并返回给项目1临床团队，以通知癌症患者的护理。CLIA实验室将使用正交方法独立查询已知的可操作突变。与此同时，我们将对患者及其肿瘤学家进行纵向调查和定性访谈， 知情同意、数据提供和决策过程（项目3）。完成后，我们将配置一个临床形式主义，肿瘤学家将基因组信息纳入他们的管理计划，并向癌症患者及其家属报告结果。 整个倡议将由Levi Garraway博士和Pasi Janne博士共同领导。D. Garraway（Project 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进展。Janne博士（项目1 PI）是一位翻译肿瘤学家，他的重大发现突出了基因组学在靶向抗癌药物的反应和耐药性中的作用。Steven Joffe博士（项目3 PI）在研究伦理方面做出了开创性的贡献，斯泰西格雷博士（项目3共同PI）是一位杰出的“初级研究员，专注于围绕癌症患者基因检测回归的沟通/政策问题。 整个研究团队由转化肿瘤学，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学的世界领导者组成。这些努力将共同定义一个可扩展的模型，用于将临床测序整合到癌症护理中。