Clinical sequencing in cancer: Clinical ethical and technological studies

描述(申请人提供)：自2001年人类基因组计划完成以来，人们一直对将人类基因组信息直接转化为临床实践寄予厚望。在过去的几年里，许多大型研究已经对人类DNA变异进行了分类。与此同时，DNA测序技术的进步增加了产量，降低了成本。我们现在可以广泛利用我们对人类遗传变异的知识，结合高通量DNA测序方法，进行个性化的大规模“医学重测序”，以全面揭示疾病背后的遗传机制并影响临床治疗。这种“从碱基对到床边”的翻译需要多学科的研究。华盛顿大学在临床方面处于领先地位 遗传学(Bennett、Burke、Byers、Hisama和Jarvik、Motulsky、Raskin和Sybert)、生物伦理学(Burke、Jarvik、Fullerton和特立尼达)、第二代测序、变体调用和注释(Rieder和Nickerson)、疾病基因发现(Browning、Heagerty、Jarvik、Nickerson和Rieder)、医疗信息学(Tarczy-Hornoch)和健康服务研究(Heagerty、Patrick、Regier和Veenstra)。在这个高度集成的方案中，我们结合这些优点来研究在临床上使用外源数据的各个方面。我们建议在华盛顿大学医学遗传学诊所有结直肠癌/息肉病(CRCP)基因检测临床指征的患者中进行常规治疗与增加外显子组分析的随机对照试验。我们将评估这项技术在鉴定临床相关CRCP基因突变、成本和患者衍生措施方面的有效性。经过专家的商议，确定应退回的附带发现的变体后，我们还将向参与者退回CLIA认证的结果。我们将获得结构化的 来自RCT常规护理和外展机构的受试者的反馈，以评估他们的经历。我们将进一步考虑转诊医生和使用焦点小组的患者的投入。我们将调查需要返还CLIA认证的研究结果的法律依据。我们工作的一个重要组成部分不仅是决定返回哪些结果，而且还决定如何最好地将这些基因组数据合并到医疗记录中。最后，我们将对没有发现CRCP突变的家庭进行CRCP基因发现研究；这种新的基因发现可以影响预防和治疗。

DESCRIPTION (provided by applicant): Since the completion of the Human Genome Project in 2001, there have been great expectations for translating human genomic information directly into clinically practice. During the last several years, numerous large studies have cataloged human DNA variation. In parallel, advances in DNA sequencing technologies have increased the throughput and decreased costs. We are now positioned to broadly deploy our knowledge of human genetic variation, coupled with high-throughput DNA sequencing methods, for individualized, large-scale "medical resequencing" to comprehensively reveal the genetic mechanisms underlying disease and influence clinical treatment. This "base pairs to bedside" translation requires multidisciplinary study. The University of Washington is a leader in clinical genetics (Bennett, Burke, Byers, Hisama, and Jarvik, Motulsky, Raskind, and Sybert), bioethics (Burke, Jarvik, Fullerton, and Trinidad), second-generation sequencing, variant calling and annotation (Rieder and Nickerson), disease gene discovery (Browning, Heagerty, Jarvik, Nickerson, and Rieder), medical informatics (Tarczy-Hornoch), and health services research (Heagerty, Patrick, Regier, and Veenstra). In this highly integrated proposal, we combine these strengths to investigate aspects of using exomic data clinically. We propose a randomized controlled trial of usual care vs. the addition of exome analysis in University of Washington Medical Genetics Clinic patients who have clinical indications for colorectal cancer/polyposis (CRCP) genetic testing. We will evaluate the effectiveness of this technology for the identification of clinically relevant CRCP gene mutations, cost, and patient derived measures. After deliberations by experts to identify variants that are incidental findings that should be returned, we will also return CLIA certified results to the participants. We will obtain structured feedback from subjects in both the usual care and exome arms of the RCT to evaluate their experiences. We will further consider the input of referring physicians and patients using focus groups. We will investigate the legal basis of the need to return CLIA certified research results. An important component of our work is determination of not only which results to return, but how best to incorporate these genomic data into the medical record. Finally, we will perform CRCP gene discovery studies for families without identifiable CRCP mutations; such novel gene discovery can impact prevention and treatment.