Authors: 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
Summary: 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 (WGS), exome, and RNA sequencing, 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.
Source: Cancer Discovery, 2021; candisc.1631.2020