Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers
Neerav Shukla, Max F. Levine, Gunes Gundem, Dylan Domenico, Barbara Spitzer, Nancy Bouvier, Juan E. Arango‐Ossa, Dominik Głodzik, Juan S. Medina-Martínez, Umesh Bhanot, Jesús Gutiérrez‐Abril, Yangyu Zhou, Elise Fiala, Emily Stockfisch, Shanita Li, Irene Rodriguez-Sanchez, Tara J. O’Donohue, Cassidy C. Cobbs, Michael H. A. Roehrl, Jamal Benhamida, Fiorella Iglesias Cardenas, Michael V. Ortiz, Michael D. Kinnaman, Stephen S. Roberts, Marc Ladanyi, Shakeel Modak, Sameer Farouk Sait, Emily K. Slotkin, Matthias A. Karajannis, Filemon S. Dela Cruz, Julia Glade Bender, Ahmet Zehir, Agnès Viale, Michael F. Walsh, Andrew L. Kung, Elli Papaemmanuil
Abstract
The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.