Comparative analysis of RNA expression in a single institution cohort of pediatric cancer patients
Authors: Vasquez Yvonne , Beale Holly , Sanders Lauren , Lyle A. Geoffrey , Kephart Ellen T. , Learned Katrina , Thompson Drew , Peralez Jennifer , Li Amy , Huang Min , Pyke-Grimm Kimberly , Salama Sofie , Haussler David , Bjork Isabel , Spunt Sheri L. , Vaske Olena M. 
Published: September 2024

AbstractImportanceGenomic analyses solely focused on detecting mutations do not benefit most pediatric cancer patients. Alternate genomic approaches are needed to identify additional treatment biomarkers and therapeutic targets.ObjectiveTo evaluate the performance of our Comparative Analysis of RNA Expression (CARE) pipeline in nominating druggable targets in pediatric patients with difficult-to-treat or rare cancers.Design, Setting, and ParticipantsOur cohort study, the Comparative Analysis of RNA Expression to Improve Pediatric and Young Adult Cancer Treatment (CARE IMPACT), was conducted collaboratively by the UC Santa Cruz Treehouse Childhood Cancer Initiative and Stanford University School of Medicine. From June 4, 2018, to September 24, 2020, UCSC Treehouse obtained and processed RNA sequencing (RNA-Seq) data for 35 tumor samples from 33 children and young adults with a relapsed, refractory or rare cancer. Each tumor RNA-Seq dataset underwent CARE analysis to reveal activated cancer driver pathways and nominate treatment options. We compare the CARE pipeline to other gene expression outlier detection approaches and discuss challenges and opportunities for the clinical implementation of RNA-Seq-based gene expression outlier detection for pediatric cancer patients.ExposuresPatients underwent tumor RNA-Seq analysis and standard-of-care tumor DNA profiling. UCSC Treehouse compared each patient’s tumor RNA-Seq profile with over 11,000 uniformly analyzed tumor profiles from public data repositories. These comparisons reveal candidate cancer genes and pathways that represent potential therapeutic targets.Main Outcome(s) and Measure(s)Proportion of patients for whom CARE provided useful clinical and biological information for patient care. Impact of comparator cohort choice on outlier findings.ResultsOf our 33 patients, 31 (94%) had CARE IMPACT findings of potential clinical significance. These findings were implemented in 5 patients, 3 of which had defined clinical benefit. We demonstrated that composition of comparator cohorts determines which outliers are detected and that large and diverse cohorts containing data from tumors similar to the patients produce the most clinically relevant outlier results.Conclusions and RelevanceComparative RNA-Seq analysis may identify additional cancer driver pathways and druggable targets in patients with rare or difficult-to-treat pediatric cancers relative to standard-of-care DNA profiling. This study highlights the clinical utility of CARE for pediatric tumors and underscores the need for further evaluation of this approach to improve patient outcomes.Key PointsQuestionsIs tumor RNA expression information useful for the clinical care of children with difficult-to-treat or rare cancers? How does choice of comparator cohort impact RNA expression results?FindingsIn this cohort of 33 pediatric patients, Comparative Analysis of RNA Expression provided useful clinical information for all patients; three of five patients who received treatment derived clinical benefit. We demonstrate the impact of comparator cohort composition on RNA outlier analysis.MeaningTumor RNA expression information reveals useful information for the clinical care of pediatric cancer patients. Choice of comparator cohort size and composition impacts gene expression outlier detection.