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.

Public Health Relevance

The use of exome data in clinical medicine is a transformative technology. It offers the possibility of faster, less expensive and more complete resolution of genetic diagnoses as well as personalized prevention and treatment. Here we apply a multidisciplinary team to evaluate clinical genomics applied to colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HG006507-03
Application #
8587492
Study Section
Special Emphasis Panel (ZHG1-HGR-N (O1))
Program Officer
Hindorff, Lucia
Project Start
2011-12-05
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$1,879,238
Indirect Cost
$641,580
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Evans, Barbara J (2014) The First Amendment Right to Speak About the Human Genome. Univ Pa J Const Law 16:549-636
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2014) The EGAPP initiative: lessons learned. Genet Med 16:217-24
Gallego, Carlos J; Bennette, Caroline S; Heagerty, Patrick et al. (2014) Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes. Contemp Clin Trials 39:1-8
Evans, Barbara J (2014) Economic regulation of next-generation sequencing. J Law Med Ethics 42 Suppl 1:51-66
Jarvik, Gail P; Amendola, Laura M; Berg, Jonathan S et al. (2014) Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am J Hum Genet 94:818-26
Burke, Wylie; Evans, Barbara J; Jarvik, Gail P (2014) Return of results: ethical and legal distinctions between research and clinical care. Am J Med Genet C Semin Med Genet 166C:105-11
Shirts, Brian H; Jacobson, Angela; Jarvik, Gail P et al. (2014) Large numbers of individuals are required to classify and define risk for rare variants in known cancer risk genes. Genet Med 16:529-34
Kocarnik, Jonathan M; Fullerton, Stephanie M (2014) Returning pleiotropic results from genetic testing to patients and research participants. JAMA 311:795-6
Grady, William M; Pritchard, Colin C (2014) Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol 42:124-39
Dorschner, Michael O; Amendola, Laura M; Shirts, Brian H et al. (2014) Refining the structure and content of clinical genomic reports. Am J Med Genet C Semin Med Genet 166C:85-92

Showing the most recent 10 out of 20 publications