The clinical management of patients with cancer does not entail a """"""""one size fits all"""""""" approach. In fact, studies of the genomic landscape of human cancers have demonstrated that cancers can have a multitude of mutations, a subset of which may be """"""""actionable"""""""" with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of unique and shared genetic aberrations. In particular, patients who have advanced / refractory cancer and are candidates for clinical trials could potentially benefit by identifying eligibility for """"""""targeted"""""""" drugs based on the """"""""actionable"""""""" genesin their specific tumor. Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. Thus, the translation of high throughput sequencing would support a """"""""personalized"""""""" strategy for cancer. However, the translation of clinical sequencing bears unique challenges including identifying patients who could benefit, developing informed consent and human subjects protections, outlining measurable outcomes, interpreting what results should be reported and validated, and how results should be reported. This proposal brings together expertise at the University of Michigan including clinical oncology, cancer genetics, genomic science/bioinformatics, clinical pathology, social and behavioral sciences, and bioethics in order to implement this clinical cancer sequencing project. We have focused our clinical sequencing effort on sarcomas and other rare cancers as this is an area of clinical strength at Michigan. Three integrated Projects have the following themes: Project 1) """"""""Clinical Genomic Study"""""""" will identify patients with advanced or refractory sarcoma or rare cancers who are eligible for clinical trials, consent them to the study obtain biospecimens (tumor tissue, germline tissue), store clinical data, and assemble a multi-disciplinary Sequencing Tumor Board to deliberate on return of actionable or incidental genomic results;Project 2) """"""""Sequencing &Analysis"""""""" will process biospecimens and perform comprehensive sequencing and analysis of tumors to identify point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression under CLIA/CAP guidelines;Project 3) """"""""Ethics &Psychosocial Analysis"""""""" will evaluate the clinician and patient response to the informed consent process, delivery of genomic sequence results, and use of genomic results.

Public Health Relevance

Cancer is a disease that is characterized by a wide range of molecular lesions, both common and rare. It is critical to identify the specific driving genetic mutation(s) so targeted therapies can be pursued in a rational fashion. The advance in sequencing technology now makes it possible to utilize genomic sequence data in a clinical setting to manage actionable diseases such as cancer. While the primary focus of this effort is on sarcomas and other rare cancers, the principles we learn can be applied to other more common cancers and human diseases.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
1UM1HG006508-01A1
Application #
8517276
Study Section
Special Emphasis Panel (ZHG1-HGR-N (J2))
Program Officer
Hindorff, Lucia
Project Start
2013-07-19
Project End
2017-05-31
Budget Start
2013-07-19
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,992,227
Indirect Cost
$680,120
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Datta, Jharna; Damodaran, Senthilkumar; Parks, Hannah et al. (2017) Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398. Mol Cancer Ther 16:614-624
Davis, Elizabeth J; Wu, Yi-Mi; Robinson, Dan et al. (2017) Next generation sequencing of extraskeletal myxoid chondrosarcoma. Oncotarget 8:21770-21777
Gornick, Michele C; Scherer, Aaron M; Sutton, Erica J et al. (2017) Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing. J Genet Couns 26:122-132
Tran, Dustin; Camelo-Piragua, Sandra; Gupta, Avneesh et al. (2017) Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor. J Pediatr Hematol Oncol 39:e466-e469
Mody, Rajen J; Prensner, John R; Everett, Jessica et al. (2017) Precision medicine in pediatric oncology: Lessons learned and next steps. Pediatr Blood Cancer 64:
Ryan, Kerry A; De Vries, Raymond G; Uhlmann, Wendy R et al. (2017) Public's Views toward Return of Secondary Results in Genomic Sequencing: It's (Almost) All about the Choice. J Genet Couns 26:1197-1212
Bruzek, Amy K; Zureick, Andrew H; McKeever, Paul E et al. (2017) Molecular characterization reveals NF1 deletions and FGFR1-activating mutations in a pediatric spinal oligodendroglioma. Pediatr Blood Cancer 64:
O'Daniel, Julianne M; McLaughlin, Heather M; Amendola, Laura M et al. (2017) A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet Med 19:575-582
Rasmussen, Luke V; Overby, Casey L; Connolly, John et al. (2016) Practical considerations for implementing genomic information resources. Experiences from eMERGE and CSER. Appl Clin Inform 7:870-82
Amendola, Laura M; Jarvik, Gail P; Leo, Michael C et al. (2016) Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 98:1067-1076

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