Abstract 4890: A pan-cancer analysis framework for incorporating gene expression information into clinical interpretation of pediatric cancer genomic data
Authors: Morozova Olena , Newton Yulia , Shah Avanthi Tayi , Beale Holly , Lam Du Linh , Vivian John , Bjork Isabel , Goldstein Theodore , Stuart Josh , Salama Sofie , Sweet-Cordero E. Alejandro , Haussler David 
Published: July 2017

Genomic characterization used in pediatric cancer clinical trials is limited to the detection of somatic mutations and gene fusions in well-characterized cancer genes. However, these approaches do not reveal actionable therapeutic targets for the majority of pediatric cancer patients. Incorporation of gene expression information into clinical genomic analysis is hindered by the lack of appropriate computational methods, designed for single patients rather than patient cohorts. UC Santa Cruz Treehouse Childhood Cancer Initiative (treehousegenomics.soe.ucsc.edu) enables the incorporation of gene expression information into the genomic evaluation of pediatric cancer patients. We leverage large cancer RNA sequencing datasets, including The Cancer Genome Atlas, Therapeutically Applicable Research to Generate Effective Treatments, Medulloblastoma Advanced Genomics International Consortium, International Cancer Genome Consortium, and published research and clinical studies. Through our “pan-cancer analysis”, we compare each prospective tumor’s RNA sequencing and/or mutational profile to over 11,000 uniformly analyzed tumor profiles using our Tumor Map method. Tumor Map visualizes single tumors together with the reference compendium and identifies samples that are most similar to the given tumor based on the gene expression profiles. We also developed a gene expression outlier analysis to identify transcripts that are over expressed in the given tumor. These pan-cancer gene expression analyses are used in conjunction with mutation data to nominate molecular pathways that may be driving the disease in each child, providing useful information to the medical teams. We aim to evaluate this approach in partnership with pediatric cancer clinical genomic trials at Stanford University, UC San Francisco, Children’s Hospital of Orange County, University of Michigan, Children’s Mercy Hospital, and British Columbia Children’s Hospital. The analysis of the first 27 patients at Stanford, most with refractory solid tumors, provided evidence of the potential clinical utility of incorporating gene expression information into the genomic evaluation of pediatric cancer patients. In all cases, we identified candidate driver molecular pathways that could be targeted by existing FDA-approved therapies or therapies available through a clinical trial. The most frequently identified molecular targets were receptor tyrosine kinases and cyclin-dependent kinases. For 3 patients with no treatment options prior to our work, the analysis contributed to treatment decisions. This study provides a framework for incorporating gene expression information into the clinical interpretation of pediatric cancer genomic data. We underscore the importance of releasing the data to the community immediately following generation, so that they may benefit new patients.

Citation Format: Olena Morozova, Yulia Newton, Avanthi Tayi Shah, Holly Beale, Du Linh Lam, John Vivian, Isabel Bjork, Theodore Goldstein, Josh Stuart, Sofie Salama, E. Alejandro Sweet-Cordero, David Haussler. A pan-cancer analysis framework for incorporating gene expression information into clinical interpretation of pediatric cancer genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4890. doi:10.1158/1538-7445.AM2017-4890