Abstract 642: Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer
Authors: Wheeler David A. , Newman Scott , Nakitandwe Joy , Kesserwan Chimene A. , Azzato Elizabeth M. , Rusch Michael C. , Shurtleff Sheila , Bahrami Armita , Orr Brent , Klco Jeffery M. , Hedges Dale J. , Hamilton Kayla V. , Foy Scott G. , Edmonson Michael N. , Thrasher Andrew , Gu Jiali , Harrison Lynn W. , Wang Lu , Mostafavi Roya , Kubal Manish , Maciaszek Jamie , Clay Michael , Ouma Annastasia , Silkov Antonina , Liu Yanling , Zhang Zhaojie , Liu Yu , Brady Samuel W. , Zhou Xin , Wilkinson Mark , Rahbarinia Delaram , Knight Jay , Wang Jian , Mullighan Charles G. , McGee Rose B. , Quinn Emily A. , Gerhardt Elsie L. , Taylor Leslie M. , Nuccio Regina , Valdez Jessica M. , Hines-Dowell Stacy J. , Pappo Alberto , Robinson Giles , Johnson Liza-Marie , Pui Ching-Hon , Ellison David W. , Downing James R. , Zhang Jinghui , Nichols Kim E. 
Published: July 2021

Abstract
Clinical genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. In the Genomes for Kids study (NCT02530658) we used a three-platform sequencing approach, including whole genome (WGS), whole exome (WES) and RNA sequencing, to examine tumor and paired germline genomes from prospectively identified children with cancer. The goal of the study was to assess the potential of comprehensive next generation sequencing to elucidate the molecular mechanisms underlying tumor formation and investigate the potential of this information to influence clinical decision-making.The cohort, with a median age of 6 yrs, range 0 - 26 yrs, included 301 patients with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type or stage. Patients with hematologic malignancies accounted for 41% of cases, 31% had CNS tumors, and 28% had other non-CNS solid tumors. This cohort also included 18 patients with very rare tumor types, defined here as occurring in less than 2 cases per million person per year.Two hundred fifty three patients (84%) had sufficient tumor for three-platform sequencing and all 301 had adequate paired germline samples. Following analysis, 86% of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer predisposing (18%) variants. The inclusion of WGS enabled detection of oncogenic gene fusions, as well as 22 cases in which oncogenes were activated through enhancer hijacking, a particularly frequent occurrence in hematologic malignancies. In addition, WGS effectively detected clinically relevant small intragenic deletions (15% of tumors) and a variety of mutational signatures, which were not detectable through analysis of whole exome data. Evaluation of 56 pathogenic germline variants in the context of paired tumor sequence data helped establish the disease relevance of several genes that are not typically associated with the cancer type in question, providing critical insights on a case-by-case basis. Examples include a pathogenic germline variant in MUTYH in a patient with retinoblastoma whose tumor exhibited a mutation signature associated with reactive oxygen species indicative of loss of MUTYH function; and conversely, a likely pathogenic variant in PMS2 in a rare brain cancer, which did not exhibit a mutation signature associated with microsatellite instability. This study successfully demonstrated the power of this three-platform approach to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. As a result of these findings, we have incorporated this three-platform approach into our routine real-time clinical service at St. Jude Children's Hospital.
Citation Format: David A. Wheeler, Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, Michael C. Rusch, Sheila Shurtleff, Armita Bahrami, Brent Orr, Jeffery M. Klco, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Jiali Gu, Lynn W. Harrison, Lu Wang, Roya Mostafavi, Manish Kubal, Jamie Maciaszek, Michael Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Mark Wilkinson, Delaram Rahbarinia, Jay Knight, Jian Wang, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Elsie L. Gerhardt, Leslie M. Taylor, Regina Nuccio, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols. Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 642.