Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing
Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, David A. Wheeler, Michael Rusch, Sheila Shurtleff, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Armita Bahrami, Brent A. Orr, Jeffery M. Klco, Jiali Gu, Lynn W. Harrison, Lu Wang, Michael R. Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Ti-Cheng Chang, Manjusha Pande, Eric Davis, Jared Becksfort, Aman Patel, Mark R. Wilkinson, Delaram Rahbarinia, Manish Kubal, Jamie L. Maciaszek, Victor Pastor, Jay Knight, Alexander M. Gout, Jian Wang, Zhaohui Gu, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Regina Nuccio, Roya Mostafavi, Elsie L. Gerhardt, Leslie M. Taylor, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto S. Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols
Abstract
Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.